Bacteria – Microbiology | Lecturio

[Music] hello and welcome to bacteria we're going to dive a little bit deeper into how bacteria cause disease and after you've watched this video you will understand the extent origin and functions of the human microbiome you'll appreciate the ways that bacteria enter and spread in their hosts they'll be familiar with the different types of bacterial toxins and their activities and you will know the mechanisms of action of members of the different classes of antimicrobials and how resistance emerges before we talk about bacteria that cause disease it's very important to first discuss the human microbiome all of the microbes that live in and on us we're how to trillions of microbes trillions and that's what we call the microbiome and it's a composition of all the microbes that are everywhere in us and on top of us a human body is only 25% human cells now look you can see me you think you're looking at just human cells 75% of what you see here are bacteria very very little human cells bacteria fungi and archaea it's amazing wherever the human body is exposed to the outside world there's a microbial community the mouth the lungs the GI tract the urogenital tract the skin and probably other places we haven't even found it yet this microbiome is just beginning to be unraveled in terms of what it does for us it certainly helps us to extract energy and nutrients from the food we eat but it also appears to inhibit the growth of pathogens not only in us but on our skin the microbes on our skin produce antimicrobial compounds that protect us it's remarkable there's probably much more that the microbiome does for example recently it's been shown in animals that the microbiome helps their immune system to develop really really remarkable in the coming years we'll be able to sort all of this out but it's quite clear from the very early days of our existence when we're first born our microbiome forms and it has a huge impact on our health microbes contribute an extra 2 million genes to the 20,000 or so genes that our human genome encodes 99% of our genes are bacterial isn't it remarkable our microbiome weighs 2 and 1/2 pounds that is weight you'll never be able to get rid of you can try and lose some of your body fat but that two and a half pounds of microbiome needs to stay with you otherwise you're going to be very unhealthy and don't forget the viruses all those bacteria and fungi and archaea in us they also are accompanied by their viruses in fact viruses outnumber bacteria by about 5 to 1 in US and it's quite clear that they have major roles in regulating the microbiome the volume of the microbiome is about 3 pints the next time you drink 3 pints of beers I want you to remember you've just drunk the volume of your microbiome it's my way of getting you to remember what I'm telling you here now where do you get this microbiome there are many ways while you're developing in utero you are bathed in amniotic fluid provided by your mother and of course it's going into your mouth and on your skin and it's got bacteria and viruses in it so that's your first encounter you're acquiring your microbiome in utero then as you are born you acquire more of your microbiome during birth if you so happen to have been born by passage through the birth canal you will start to acquire the bacteria that are present along that canal not just in your mouth but on your skin people who are born by cesarean section they don't go through the birth canal of course they come out through an opening in the skin produced by surgical manipulation they have a very different skin microbiome from children who are born vaginally so it's probably better to be born through the normal routes you acquire probably a more beneficial microbiome of course in some cases it's not possible for health reasons you also acquire a good amount of your microbiome from your mother your mother is one of the first to hug and kiss you and she continues to do so hopefully for the rest of your life and your father also contributes and any caregivers who may come into your home they are all contributing to your microbiome breast milk is a very important contributor to your gut microbiome again breastfeeding is not done by everyone but it's been shown in many studies to be better indicators of subsequent health you also acquire microbiome from the soil that you may touch you should let your kids play in the soil it's probably good for them to help acquire their microbiome from the water that you wash yourself in and drink from the foods that you eat and any people or pets or plants that you encounter early on in your life the early years are formative years and then you acquire a relatively stable microbiome that is very similar to that of your family and only when your health changes or if you move or change your diet do you change your microbiome and the consequences of the microbiome for human health are going to be learned in the next 10 years and we're really going to find out fabulous ways that we can improve our health by manipulating it okay on to infection basics let's talk about some principles by which bacteria can enter the host we can divide bacterial infections into two broad groups depending on how they're acquired some are acquired exogenously from some external source like bacteria in the environment or bacteria in the food the water the air the objects we touch insect bites where any animals dog bites for example and so those are exogenous exogenously acquired from elsewhere and that contrasts with endogenously acquired infections where our microbiome suddenly turns on us and this could be because we've altered the microbiome by treatments with antibiotics and cluster ideo infections of the intestine or a great example of that where we alter the composition of this family of microbes and then suddenly cost really over grow and cause us problems sometimes injuries introduce skin bacteria into us and this is commonly occurring with staphylococci normal inhabitants of the skin when an injury introduces them below the skin this can cause a problem so we get bacteria that cause infection is an illness from external sources and from within ourselves let's talk a bit about how bacteria gain entry to the host the exogenous sources of infection here's a human body which provides a very large spectrum of places for bacteria to enter a very common place is a mucous membrane we have mucous membranes all throughout our body our eyes our mouth and nose the entire alimentary tract which is essentially a very long tube starting from our mouth going through our intestines and out the anus that is all lined with mucous membranes because it has to absorb food and excrete waste and because it's a mucous membrane it is vulnerable it is not sealed against entry things like breathing eating having sex all can introduce pathogens into us cholera whooping cough and gonorrhea are example of bacterial infections that are acquired across mucosal membranes now we are happen to be covered by a wonderful protective organ called the skin the skin is the biggest organ in your body it weighs the most and it has the most square area and it is a great barrier the outer layer of your skin is dead so viruses cannot multiply them they have to get inside by penetration but there are ways that the skin can be breached allowing bacteria to invade the underlying cells in tissues how can this happen insect bites of course they routinely deliver things below the skin any kind of scratch or injury which we're all prone to having will also breach that wonderful protective barrier once you're in a mucosal membrane there are ways to get across that which are even easier than in the skin you typically don't need an injury here's a cross section of the intestinal mucosal barrier and on the left side is the lumen of the gut the space on the interior and the first line of defense is an epithelial cell barrier and below that are the submucosal tissues and that also contains capillaries and lymph capillaries so if a pathogen can get across the epithelial cell sheet it has access to the circulatory system which can bring us and bring it anywhere and of course below that are the muscle cells that help to contract the intestine during digestion if we take a closer look at this intestinal lining we can see that there are different kind of cells that make up that epithelial sheet there are Antero sites which are involved in taking up nutrients and then interspersed among them are the so-called M cells in which immune cells come from below lymphocytes and macrophages and sample the contents of the gut to make sure there is nasty they're both the Enduro site and the emcell can be points where pathogens can cross into the underlying tissues once a bacteria has adhered to the epithelium which many do as we'll talk about later they can move laterally reproduce and move across two contiguous tissues or as I said they can penetrate the epithelial sheet and disseminate to distant sites our immune defenses play a big role in limiting such incursions but they don't always win and bacteria do enter the rest of our body once a bacteria or many bacteria are in us they typically multiply in order to cause disease and this graph shows a time course of some typical infections the x-axis shows you time and the y-axis shows you various parameters including the production of bacteria and red and immune responses so there is a period initially after the bacteria enter us called the incubation period this is an extremely point important concept this is a period which is variable among the different infections during which the bacteria are multiplying but we don't yet have overt disease during that period immune responses may be mounting but again and you may have you may have fever as a consequence of that chills aches and so forth but you won't have the actual symptoms of the disease that is the incubation period then as the bacteria multiply they may either elaborate toxins or they may invade and cause tissue damage you have a period of disease and if you follow the red line and go above the blue segment of this graph that says no disease above the blue is where we have bacterial disease and this can be a consequence of both the immune response and direct effects of bacterial toxins which we'll talk about in a moment on us there is a very important part of this graph which shows no disease some bacterial infections where the bacteria are replicating will not result in disease these are called asymptomatic infections and many people have these it's a consequence of them being able to control the replication of the bacteria and others may have simply more resistance to disease formation and the outcome of course of a bacterial infection can be recovery and cure and subsequent immunity it can be unfortunately in many cases death or in some cases immunity is not lifelong and we obtain recurrent illnesses with the same pathogens let's talk a bit about bacterial toxins these are molecules produced by various bacteria that alter the normal metabolism of host cells and they are often responsible for the major symptoms of bacterial infection and there are many different kinds of toxins that are produced which we'll talk about briefly interestingly this is in direct contrast to viral infections in which very few viral toxins have been identified they cause disease in very different ways from bacteria now we recognize different classes of bacterial toxins some are called EXO toxins because they are secreted by the bacterium into the extracellular environment these exotoxins shown on this picture have a typical a B structure they have subunits separate subunits consisting of an A component and a B component typically the way they work is they're secreted by the bacterium and they bind a receptor shown here in our on the surface of the eukaryotic cell on the surface of our cells they are then taken up into the cell by the end acidic pathway and typically the a component which is the active component is released from the receptor binding component makes its way into the cytoplasm where then has its effect on cells there's another class of toxins called the type 3 cytotoxins they're shown on the right of the diagram where we see an outline of a rod-shaped bacterium and what looks like a syringe injecting molecules into the host cell those are type three sight aqaq toxins are directly injected into the host cell by a structure on the bacterium called a secretory injection system and these have evolved just to inject toxins into the cell these secretory systems act by introducing molecules into cells to alter their behavior other toxins are produced by bacteria that act at the surface of host cells some of them bind to pattern recognition receptors and induce the production of cytokines which have lethal effects there are also pore forming toxins which make holes in cell membranes and make them die and finally there are toxins called super antigens that bind to t-cell receptors and major histocompatibility receptors and induce the synthesis of many many toxic cytokines and finally there are proteins called EXO enzymes produced by bacteria that modulate targets in the extracellular matrix let's look at toxins in a bit more detail I mentioned that they typically have an a/b structure the diphtheria toxin is consists of one molecule of the a and one molecule of the B again the B is the receptor binding component the a is the effector portion that actually has an effect on the host cell the theory of toxin the a portion blocks cell protein synthesis the a portion adp ribosylation initiation and the elongation factor for translation eef2 it stops host cell protein synthesis and kills the cell cholera toxin is composed of a single a subunit and 5b subunits this toxin elevates intracellular cyclic adenosine monophosphate in the epithelium of the small intestine and that causes movement of fluid into the lumen and the classic diarrhea associated with cholera and finally the anthrax toxin the highly lethal anthrax toxin is composed of two a in a b subunit and again the b subunit binds the cell receptor to toxins that are well known botulinum toxin produced by C botulinum and tetanus toxin produced by C teton eye Clostridium are neurotoxins these toxins elaborated by the bacteria at different sites make their way through the circulatory system and the lymph system to the brain where they cause their effects tetanus toxin for example causes muscles to contract uncontrollably and they cause what we call paralysis on the other hand botulinum toxin blocks muscle contractions so the muscles get flaccid this is called flaccid paralysis so two very different effects on the central nervous system the type 3 site of toxins we mentioned briefly before they're shown on the right-hand part of this screen they are injected by the bacterium into the host cell by a type 3 secretion apparatus bacteria have a number of different kinds of secretion apurate which are used to inject effector molecules into the host cell to get them to do what they want and these have their own ways of altering the biochemistry of the cell to cause pathology type 3 sided toxins are found in a wide range of bacteria for example Salmonella Shigella suna Mona's cholera and the plague bacillus all produce type 3 toxins of various sorts and we'll mention a few of these and how they work in a few moments another toxin and a very important one produced by gram-negative bacteria is endotoxin now if you don't remember what a gram-negative bacteria is go back to the introductory bacterial lecture and take a look endotoxin is sort of like the calling card of gram-negative bacteria it announces to the host I'm here and you better watch out the endotoxin is nothing more than lipopolysaccharide that outer layer on the outer membrane of a gram-negative teria so that outer layer is a lipid bilayer but the outer layer is unusual it's not the standard kind of lipid it's made of lipopolysaccharide and that is what is endotoxin now despite the name endotoxin this toxin is not internalized into the host cell it remains extracellular Lea it just happens to be the name that has stuck over the years let's look in closer at that outer membrane that lipopolysaccharide here it is in some detail remember the very bottom there are lipid chains that form the outer leaflet of that membrane and that component is called lipid a that's the active component of endotoxin that is what has the biological effect and then there are other portions including the portion that we talked about which extends above completing lipopolysaccharide lipopolysaccharide is recognized by pattern recognition receptors located on the surface of the eukaryotic cell we all have such receptors in order to for us to recognize what is foreign and when foreign molecules are recognized the result is a production of cytokines which mobilize the immune response but may also have detrimental properties so on the left of this slide are three pattern recognition receptors one of which recognizes LPS that portion of the outer membrane of bacteria that we've just been talking about another one FLA recognizes flagellin the protein that makes up the flagella of bacteria that helps them to move so here's a close-up look of the pattern recognition receptor and it again recognises endotoxin as being present initiates cytokine synthesis and depending on how much endotoxin is present low or high it has different effects on the cell so you can imagine that early in infection it has one kind of effect where the endotoxin is low and then if the infection proceeds unchecked you'll have higher concentration of endotoxin you will have a very it affect these receptors for endotoxin and other bacterial products are called innate receptors they also sense viral infections as well so at low concentrations of endotoxin there are a variety of effects many of which reflect the attempts at the immune system of eliminating the bacterial and infection so let's take a look at some of these you can see the four different targets here in the ultimate activities and effects of endotoxin at low concentrations endotoxin targets kupffer cells macrophages of various sorts it causes release of cytokines when it binds to its receptor cytokines are produced and some of those cytokines cause fever so endotoxin is well known to be pyrogenic fever inducing the mechanism is by being recognized by that in a receptor and producing a cytokine that induces fever cytokines endotoxin also activates macrophages it makes them more phagocytic that makes them secrete hydrolases and have just more enhanced killing the idea being of course there's endotoxin here we sense it there must be a gram-negative we're going to kill it so we're going to get activated at low concentrations endotoxin also activates neutrophils this has an effect of dilating blood vessels and allowing immune cells to come in and clear any infections that may be present and no toxin also activates B lymphocytes the lymphocytes of course produce antibodies and these may be useful for clearing the infection finally at low concentrations endotoxin also activates the complement system which whose goal is many-fold essentially trying to get rid of the bacterial infection complement can help take up bacteria into macrophages by opsonization it can increase capillary permeability and it can also poke holes into bacteria all of this is part of the inflammatory response to infection now in contrast at very high levels of endotoxin it often can result in shock fluid loss for example caused by too many cytokines and disseminated intravascular clotting or coagulation there are other membrane damaging toxins as well lipase is for example enzymes that digest lipids an example is the lecithinase from Clostridium species this enzyme can lyse cells and eliminate defenses and provides nutrients for bacteria these are bacterial toxins licen eukaryotic cells to avoid defenses and the life cells produce nutrients for the bacteria he mollison's can release red and white blood cells and then there are toxins that form pores in the cell membrane they insert into the membrane they allow water to flow in and the cell bursts again a way for bacteria to avoid some of those immune cells that are trying to get rid of the bacteria we also have what are called heterogeneous pore forming toxins these are produced by a variety of bacteria one well-known one is streptomycin Oh produced by the streptococci this pore forming toxin binds cholesterol and damages lipeh somes in cells of the host causes the cells to lyse part of the reason why tissues are damaged another set of toxins that are produced and if you're thinking boy bacteria make a lot of toxins you're right this is their modus operandi so these are called extracellular matrix toxins the extracellular matrix is the area between cells here on this picture we're showing two cells and the area between them and below them this is filled with all kinds of substances that provide protection and hold the cell together this is the extracellular matrix bacteria produce enzymes called hyaluronidase hyaluronic acid is a component of the extracellular matrix as you can see here and this breaks it down it breaks down connective tissue allowing bacteria to spread better streptokinase is an enzyme produced by streptococcus I it activates plasminogen converts it to plasmin which then attacks blood clots and gets them to dissolve bacteria don't like blood clots because it didn't hit stem from moving about and may restrict them so this enzyme takes care of that and finally collagen aces and elastase --is also digest the extracellular matrix allowing free flow movement of the bacteria I'd like to end up this discussion by talking about antimicrobial compounds that are used to treat bacterial infections and think we have a bacterial infection in us we need to treat them with drugs that will kill the bacteria but will not harm us in other words the antibiotics or antimicrobial compounds have to be selective they have to target things in the bacteria that are not present in ourselves fortunately this is relatively easy to do because bacteria are very different from eukaryotic cells I'll give you an example of such selectivity there is a class of antibiotics called the beta-lactam antibiotics and these include the penicillins the cephalosporins and the carbapenems there's they're called beta-lactam antibiotics because they have a chemical ring in them called the beta-lactam ring these antibiotics target the synthesis of murine now do you remember from an earlier lecture what marinas and gram-positive bacteria this forms a thick layer on the outside of the bacterium just above the cell membrane and it's composed of sugar molecules joined together and cross linked by amino acids of short length and the right of this slide is a diagram of the synthesis of murine murine is exclusive to bacteria it does not occur in eukaryotic cells and on this slide are four different antibiotics fosfomycin cyclo serine vancomycin and penicillin which block different steps on the synthesis of murine so these antibiotics work beautifully because murine is only in bacteria and not in ourselves so they have very very little toxicity you can see we have developed over the years antibiotics that target different steps in the synthesis of murine including penicillin that last step which is assembling the cross-linking amino acids between the sugar chains unfortunately as as we develop new antimicrobial compounds resistance to them rapidly emerges and today we have resistance to almost every antimicrobial compound that we have developed and the situation is becoming dire because we have fewer and fewer options with which to treat bacterial infections antimicrobial resistance occurs in nature at its ancient bacteria make antibiotics to compete with each other in nature and many of those we have harnessed to use as antimicrobial treatments of infections of people we know that these genes that confer resistance have been around for thousands and thousands of years we can find them in very old sites on earth and there's plenty of evidence that they existed way before humans developed an t-mike antimicrobial compound so we're really taking advantage of something that exists in nature there are a number of mechanisms by which these antimicrobial genes or I should say antimicrobial resistance genes work for example they may direct the synthesis of an enzyme that breaks down the drug a simple way of doing resistance they may chemically modify the drug so it interferes with its function they could inhibit the uptake of the drug into cells and tissues so it can no longer access its target or they could stimulate the export of the drug from the bacterial cell so it's no longer bacteria seidel or they may modify the target site of the drug so there are many different mechanisms of antimicrobial resistance and again these are all encoded on genes that code for proteins that have these various activities let's take an example to illustrate that and we'll use example the antibiotic vancomycin its target is cell wall modification so vancomycin acts by blocking the assembly of the Marine cell wall now at the top of this slide is the normal incorporation of the precursors of murine so the blue and the green ovals those are sugar molecules that are going to be part of the growing peptidoglycan chain and this smaller ovals below them those are amino acids that will eventually cross link the murine to make it very strong so the way this works is that subunits are added to the growing chain and the second part of this in the second row of this diagram you can see the growing polypeptide chain vancomycin binds to the precursors by binding to the amino acid vancomycin is shown here in purple with the V or maybe that's brown and it's binding the amino acids and blocking the incorporation into the new chain therefore this inhibits marine synthesis and kills the bacteria resistance to vancomycin one mechanism of resistance is simply that the bacterium changes the D al ideale to D Allah D Lac and lactose can be incorporated into this chain it invades vancomycin resistance and the antibiotic no longer works that's one example of the way resistance works going back to our beta-lactam antibiotics which i mentioned before and the arrow points to the beta-lactam ring that's common to all members of this class that's why we call them beta lactams we have so far identified over 300 beta lactam aces these are enzymes that cut that beta-lactam ring and these beta lactam aces encode resistance to the beta-lactam antibiotics so you can see the extent of the problem beta lactam aces are everywhere further complicating antibiotic reason since is that the genes encoding resistance factors for example that encode beta lactam aces are often able to move from bacterium to bacteria one way to do that is via plasmids and in fact many of these antibiotic resistance genes are encoded on plasmids this diagram which we saw previously and one of our other lectures shows how plasmids can move from one bacterial cell to another and the upper left is the bacterial cell with a chromosome in green and a smaller plasmid in red let's say this plasmid encodes a beta lactamase which confers resistance to beta lactams to that bacterium well in the second set of bacteria the two bacteria now exchanging DNA through a plist that's joining the two cells and the plasmid is moving from one cell to another the result is that that second cell now acquires antibiotic resistance so you know problem here is that we we often fee feed our animals that we eat for food lots of antibiotics so they grow quickly the effect is that we select for antimicrobial resistance and the animals and then when we eat these foods we acquire antibiotic resistance genes in us which are of no consequence initially but then when we go to have surgery and we need antibiotic therapy it doesn't work because we have the resistance already in us so these antibiotic resistance genes can move around bacteria extensively this is why they're a problem not just by plasmid mobility but by also movement by transduction the exchange of pieces of DNA by viruses or simply by naked DNA so gene transfer among bacteria we call this horizontal gene transfer is widespread and is a big problem for antimicrobial resistance and let's end up with a chart showing you some common mechanisms of resistance to antimicrobial agents for example the penicillins and the cephalosporins are hydrolyzed by beta lactamase a--'s which we mentioned these resistance genes are in fact carried on plasmids the cylinders is a change in the penicillin penicillin binding protein not Anna beta-lactamase but in a separate protein this happens not to be carried on a plasmid tetracycline resistance encodes a pump that pushes the drug out of the bacterial cell this is a plasmid born resistance factor so if you look at all these various mechanisms of resistance modification of the drug synthesis of alternate substrates and so forth acetylation change in binding sites look how many are encoded on plasmids and that simply means that they're easy to go from bacterium to bacterium and we have a hard time treating bacterial infections when these resistance genes are so mobile hello and welcome to bacterial infections today we're going to talk about Staphylococcus and streptococcus and when you listen to this lecture you'll be able to know the structure and virulence factors produced by the staphylococci and the streptococcus I you'll be familiar with the pathogenesis and the epidemiology of diseases associated with Staphylococcus I and streptococcus I you'll know which drugs can be used to treat staphylococcal and streptococcal infections and you'll become acquainted with the available streptococcal vaccines let's dive into staphylococci first these are causative agents of abscesses and toxin mediated diseases here we have a photograph of Staphylococcus aureus these are grand positive cocci and they're often called grape like clusters so if they look like grapes to you purplish so that's the morphological appearance of Staphylococcus I staphylococci colonize the nose and other mucous membranes and the skin of 30 to 40 percent of humans 30 to 40 percent of people are carrying these bacteria as part of their normal flora not everyone all right but some of them do in your nose mucous membranes even on your skin these bacteria nevertheless under some situations can cause a variety of diseases they include focal abscesses and what we mean by that is an abscess in a very specific place like on the skin where it would be a boil many of you may have had boils before focal infections a very raised pus-filled lesion we'll see some of these in a moment and but these can also occur inside of you not just on your skin for example in your lungs bones other organs kidneys and heart a general feature of the staphylococci is that they secrete potent exotoxins we talked about exotoxins in a previous lecture on bacteria these are proteins that are produced and elaborated from the bacteria that have effects on the host in the case of staphylococci these include the toxic shock syndrome toxin staphylococcal scalded skin syndrome and food poisoning these are all a consequence of the production of toxins the toxic shock the scalded skin the food poisoning are all consequences of toxin production and their effects so among the toxins that staphylococci produce are lipases and hydrolases these have as an effect to degrade the lipids of your skin and that in part contributes to the production of these boils these staphylococci can spread from person to person via aerosols respiratory spread produced by coughing or sneezing or even talking did you know that as I'm speaking now I'm actually making an aerosol and so if you are standing right in front of me you could be infected and it's in particular letters like pee pee where I'm sending out puffs of aerosol that's one way that people can spread I don't have to sneeze or talk or coffee so person-to-person by respiratory aerosols or by direct contact these bacteria can be transmitted of course if you already have the staphylococci this is not relevant but as I said there are many people who don't have them and they can acquire them from others by these routes of transmission now as I said before they're on a certain percentage of humans on the skin and they remain there harmlessly typically and they don't penetrate unless there's damage to the skin you have a cut that pushes the staph aureus deeper and it can then cause an infection or in a mucous membrane as well if you have a cut in the inside of your mouth that may introduce the bacteria into deeper tissues where it can then cause a problem so if they are left in their normal places they're okay and problems arise when there are damages occurring so things like burns wounds of various sorts lacerations even an insect bite certainly surgery variety of skin diseases all these conditions can let staph aureus comment when you have surgery either one of the first things they do is to extensively wash the skin where you're going to be cut with a preparation to sterilize the area or reduce the number of bacteria if that's not done properly the staph aureus will be introduced into the wound and you can have serious infections of the sort that we're going to talk about so let's look at an abscess here's a photograph of a man you may think that this is in fact a nipple but it's not it's an abscess caused by a staphylococcal infection the nipple is a little bit south of this boil on his chest so this is an example of a boil caused by a staphylococcal infection many people have had these here the infection remains localized it is in this boil and it doesn't go beyond that this boil contains pus and that's called an abscess or a fir uncle interesting word for uncle is one boil like this a carbuncle is when you have several boils together makes a larger structure for uncle carbuncle so this is the this is a typical boil we call them colloquially or an abscess when the bacteria spread beyond the initial boil in subcutaneous or sub mucosal tissues this is called cellulitis so the staphylococcal infection when it spreads beneath the skin cellulitis as you might predict one of the main immune defense cells important for regulating Staphylococcus replication and spread are neutrophils these maintain a balance of the bacteria in normal people and if your neutropenic that can be a problem in controlling staphylococcal infections very early an infection so let's say you have a cut you and that introduces the Staphylococcus eye which you happen to have on your skin into deeper tissues there is a battle between the bacteria and your immune system involving neutrophils and other cells early in the infectious process many neutrophils are killed by the bacteria and these release lysosomal enzymes the neutrophils are full of them it's part of their armamentarium for killing bacteria when the neutrophil dies they're released into the tissue and those enzymes then damage your tissue and they contribute to the formation of a boil let's take a little bit of a deeper look at what this Boyle actually is or abscess in more precise terminology so here is a diagram of the abscess on this slide an abscess is walled off with a capsule made of fibrin this is a host reaction to the bacteria the host makes a fibrin capsule to try and restrict the bacteria to this one place now the consequence of this is that the bacteria are also isolated from the immune response so it's actually a consequence both of host and bacterial action within this boil or abscess we have dead neutrophils which are killed by the bacteria and this produces the pus we have epithelial cells we have bacteria and fluid and so this grows to a certain size is painful to a certain extent and that's what an abscess looks like staph aureus makes a number of what we call virulence factors these are toxins and other proteins that are made that help it to spread and overcome host defenses and there are a number of them in the center of that slide there are the staphylococci and you can see elaborating a variety of proteins like leukocidin x' he mollisons protein a coagulase --is and proteins that help make fibrin clots dissolve let's look at some of these in some detail let's take a look at some of the virulence factors produced by Staphylococcus I these are grand positive bacteria with a thick outer wall of peptidoglycan and surrounding that is a capsule which you may remember from our basic discussion of bacteria the capsule is important for inhibiting phagocytosis in this picture we have a macrophage trying to take up the Staphylococcus and the capsule will inhibit that reaction will resist it's because of course once the bacteria is inside of the cell it could be destroyed the outer surface of the bacteria just below the capsule consists of peptidoglycan which you remain remember is alternating chains of carbohydrates cross-linked with short peptides this product of the Staphylococcus activates complement this is a host defense against infection and complement will have various inflammatory procedures it will cause lysis of the bacteria and production of cytokines and so this is part of the inflammatory reaction that goes on inside the carbuncle the bacteria also make a protein called protein a this is quite an interesting protein in the diagram you can see the protein a is on the surface of the bacterium it's shown in that little green box what this protein does is bind the FC portion of antibody molecules so that you know antibody molecules are I shaped molecules the FC is down at the bottom and the antigen binding sites are at the top normally your antibodies would bind the Staphylococcus but the Staphylococcus is binding the antibody the other way so it can't bind the bacterium and this reduces the ability of the bacterium to be taken up into macrophages by opsonization very clever strategy for avoiding that process the cap sue the catalase is produced by Staphylococcus I this is an enzyme that Cleaves hydrogen peroxide that's hydrogen peroxide h2o2 shown right there hydrogen peroxide is produced by cells like macrophages it's it's product is to destroy bacteria bacteria in turn make an enzyme called catalase and this will cleave the hydrogen peroxide to evade destruction very clever the bacteria also produced an enzyme called coagulase which converts fibrinogen to fibrin and that helps to make a clot that surrounds the boil and isolates the bacteria from the immune response and Staphylococcus I also make pore forming toxins like he mollison's leukocidin x' and hyaluronidase --is that digests the extracellular matrix all of these in an effort for the bacteria to spread and avoid host defenses we've talked about many of those before staphylococcal infections are very difficult to treat antibiotic resistance has become widespread among the staphylococcal strains that colonize us there are many beta lactam aces in these as we discussed in another lecture on general bacteria and those beta lactamase is encode resistance to the penicillin type antibiotics this what this resistance is widespread in addition the bacteria make a penicillin binding protein to a which further makes them resistant to penicillin class antibiotics and you may have heard the term mr essay or mersa to describe these this stands for methicillin-resistant Staph aureus and this is very popular in the press to talk about MRSA as a super bug because they're extremely difficult to treat almost impossible to treat with antibiotics so Marissa describes the most resistant of these strains of staph aureus so these are these are serious infections what kind of other diseases do these cause they cause staphylococcal scalded skin syndrome try and say that four times quickly this is a skin illness as you can see here and it I think the name tells you what it looked like this mainly affects neonates this is caused by sloughing of the skin the skin is coming off it's red and angry-looking caused by toxins produced by the Staphylococcus I specifically talks exfoliat 'iv toxins a and B exfoliation the loss of your skin you can also describe a disease called toxic shock syndrome TSS which became popular not very long ago this is accompanied by fever skin rash hypotension low blood pressure and also peeling of the skin exfoliation toxic shock syndrome was first described in connection with the use of highly absorbent tampons that allowed organisms to proliferate tampons went through a revolution in their production where they became extremely absorbent and also would block off the vaginal canal and the makers thought this was a great thing because it's convenient for women but it turned out that these trapped the staph bacteria in the vaginal canal allowed them to proliferate in and around the tampon and elaborate toxins and this brand-new disease that had never been seen before toxic shock syndrome suddenly was described and that's a staphylococcal disease associated initially with the use of tampons but now we know there are other causes as well one of the main toxins produced by Staphylococcus eyes that causes toxic shock is called TSST one toxic shock syndrome toxin number one and this is an anthro toxin it actually acts as a super antigen super antigens bind the T cell receptor and the major histocompatibility protein on the surface of cells and cause massive release of cytokines from macrophages and T cells that are then responsible for the symptoms say of toxic shock syndrome the whole idea of toxic shock elaborates from these cytotoxins that are produced staphylococci can also cause food poisoning we've been talking about skin diseases of various sorts but they can also be in your food and they produce enterotoxins that are in the food when you eat it these make you sick and the bacteria if they contaminate the food and you can imagine that someone may have staph aureus on their hands they're preparing food they haven't washed their hands they don't wear gloves you now have staph aureus in the food if it's not kept cold if it's at room temperature which sometimes happens during food production or serving the bacteria will grow they will produce their toxins and when you eat it you will get sick this typically happens with meats including poultry egg products salads milk and dairy products so if you ever have been to a buffet where there's lots of food spread out on the table if it sits there for hours at room temperature the bacteria can grow and make their toxins next time you go to such a function make sure the people are wearing gloves if they're not you should just stick with the wine and don't touch the food this disease when you ingest these toxins causes nausea vomiting stomach cramps and diarrhea and it's typically a rather rapid onset so food poisoning where you are eating food that has a and in it already the onset is quick so if you eat something in an hour or two later you're vomiting you can say well that could be a staph aureus toxin caused food poisoning in contrast if it takes a few days to get sick that means the bacteria have to replicate in you before you get sick so this is a rapid onset food poisoning caused by Staphylococcus I and then in two or three days you recover and then you can blame the food handlers all right those are the Staphylococcus I let's move to another caucus streptococcus I also gram-positive cocci growing in pairs or chains as you can see in this micrograph of the organism we put them into two groups there are a number of different ways to categorize streptococcus I so if you decide by listening to this lecture you want to go read about streptococcus now you may find other classifications and you will say RAC and yellow didn't know what he's talking about but but there are just many ways to do it and so I'm going to tell you one way because we can't tell you always and that is as follows there are Group A streptococcus I which goes a wide range of clinical diseases and then there are Group B which are leading causes of neonatal sepsis that has disseminated infections and meningitis I like this because it's a very simple classification and you can remember it just like the staphylococci many people carry streptococcus I in them as well this is ubiquitous in the human population it's worldwide it's in every country and it's found on the skin and the nasopharynx your nose and pharyngeal tissues of about 20% of school-aged children so if you go to any random classroom in the world about 20% of those kids have this bacteria the streptococcus I on and in them and when you do carry streptococcus I usually you're okay we say you're asymptomatic you're a carrier and you could potentially infect other people but you are okay and this is a common occurrence and when infection and disease occurs it's usually in the form of safe pharyngitis and this happen and schoolchildren so you may have a class full of kids 20 percent of them have streptococcus I'd you put them together they infect other kids who don't have the bacteria they may get pharyngitis we also call it strep throat this is a rather painful throat infection and if you get a throat infection and it's really hurting it's a good possibility that it's strep throat caused by streptococcus I'd the bacteria may also infect the skin and soft tissues causing lesions that are called pyoderma x' you can see one here on the young lady's arm pile dermal infections usually require a break in the skin to introduce the bacteria similar to the story with staphylococci all right so in the pharynx you don't require a break but on the skin here a break in the skin if you're a carrier you get an infection if you're not a carrier and you're unlucky enough to have touched someone who has streptococcus eye on your skin you'll get a pyoderma it's spread from person to person again by respiratory droplets produced by coughing sneezing or talking or by direct contact very much like the Staphylococcus I most of these streptococci remain localized either in your throat if you have pharyngitis or on your skin a pyoderma but over the last 10 or 20 years we have seen an increase in strains of streptococcus I that apparently can invade deeper tissues and this is serious and a worrisome occurrence because these are life-threatening infections so the bacteria are not just staying in the throat or on the skin but they're invading they're moving systemically and as you can see all the different organs in this young lady can be infected and these are serious infections Group A streptococcus I produce proteins that promote spread of the bacteria these are exotoxins that we've talked about before and include proteases that digest proteins in the host which would normally restrict the spread of the bacteria hyaluronidase is hyaluronic acid is a component of the extracellular matrix and this is digested by hyaluronidase it loosens up tissues and allows the bacteria to spread and DNA says there's often extracellular DNA in tissues that makes it very thick and it's difficult for bacteria to move through this they make a DNA switch chops up the DNA and allows free spread of the bacteria these bacteria also produce an enzyme called streptokinase it's shown here in 3-dimensional structure of the protein this enzyme converts plasminogen to plasmin plasma in turn degrades fibrin fibrin is a component of blood clots and it restricts bacterial movement so this is another strategy the bacteria have to move around the body the bacteria also produce strep to license two different kinds s and O these lice cells of various sorts including immune cells that are trying to get rid of the bacteria so you can see the value of that for the bacteria and that the bacteria also are very good at avoiding phagocytosis remember macrophages like cells are trying to take up these bacteria to destroy them the bacteria have on their surface and M protein it forms a dense layer on the surface of the bacteria it binds complement and inhibits uptake by the back by the macrophages the bacteria also have a capsule on the outer surface this is another anti phagocytic structure so it has at least two ways to avoid phagocytosis and destruction some of the more serious outcomes of streptococcal infections in particular group a streptococcal infections are non separative sequelae this means fever without pus now you remember an abscess is full of pus dead neutrophils and other things but there can also be fever and infection without pus and that's what non-supportive sequelae means one of the more serious is acute rheumatic fever this is a syndrome that can occur from 1 to 4 weeks after the initial infection so a child gets strep throat and when you if you have a child that gets strep throat you should worry immediately and and that this sequelae is going to occur rheumatic fever because it can be life-threatening way beyond the sore throat so get the infection treated this infection involves carditis infection of the heart polyarthritis infection of many joints Korea subcutaneous nodules and erythema margin autumn the inflammation of the heart is the most serious issue here this can cause scarring of the heart valves so these bacteria infect the heart the the valves get scarred and for the rest of the child's life they have heart issues because of this and this can also kill them can be a fatal infection why does this happen it happens to be an autoimmune disease we make antibodies against the bacteria as they're growing in us but some of those antibodies also recognize our heart tissue and begin to attack heart tissue and destroy it this doesn't happen in everyone and it's probably a consequence of your particular immune makeup but that's why it's an autoimmune disease rheumatic fever after stroke infection with Group A streptococcus I'd another important streptococcus is streptococcus pneumoniae a specific species of streptococcus i also known as the pneumococcus this is a famous organism on so many levels here it is in this picture it is usually eye in pairs and this bacterium was famous in research and medicine in research it's famous because it was used to show that DNA is the genetic material in 1940s in a classic experiment it's also famous because it's a very common causative agent of community-acquired bacterial pneumonia pneumococcal pneumonia what do we mean by community-acquired you go out in the community and you get it from someone else as opposed to hospital-acquired for example so this is the most common cause of that kind of pneumonia over a million deaths every year throughout the world caused by streptococcus pneumoniae so this is a serious infection there used to be many more but we learned how to control it with antibiotics humans are the reservoir for this bacterium some of us Harbor them and others do not if you happen to not have a pneumococcus in you and you are infected from someone else you may be able to deal with the infection readily you may clear it and never get sick or you may develop pneumonia lung disease and the outcome really depends on many factors including the genetic makeup of your immune system whether you have any sort of disease that would predispose you to lung disease such as another type of lung disease or if you're a smoker this often is a predisposing factor and finally we think that the strain of pneumococcus also makes a big difference some are virulent and others are less so this diplococcus or pneumococcus is spread from person to person by respiratory droplets very much like other streptococcus I so again a carrier here maybe doesn't have disease is speaking with someone who doesn't have the bacterium who may be older and compromised in some way and that person can acquire the bacterium and develop pneumonia so initially you inhale the bacteria colonizes your nasal pharynx the upper part of your respiratory tract and then it may replicate and spread down into the lungs and their cause pneumonia conditions that decrease your cough reflex are important for susceptibility to pneumonia coughing is an important way of expelling organisms in your in your mouth and nasal pharynx we also have something called a ciliary elevator in our respiratory tract our spire story tract is lined with cilia these are tiny hairs that constantly move and their function is to take any particles that you inhale and bring them back up again so your tract is lined with these cilia and it's also covered with mucus and if you inhale a particle one of your reactions maybe took off and expel it another thing that may happen if it's not very large as the ciliated elevator may bring it up goes into the back of your throat and then you swallow it and it gets digested in your stomach you do this whenever you swallow you're actually swallowing material that's come up from your respiratory tract some people spit instead you know who they are they're walking around the street spitting which is kind of a gross habit better is just to swallow it and let it get digested anyway if you smoke you inhibit that ciliary elevator you slow it down and so that's why smokers in particular have more predisposition to respiratory diseases such as this is this one the pneumococcus carries out a classic struggle with phagocytes the phagocytes want to eat it of course the bacteria don't want to be eaten they want to multiply and survive to infect another day so we have a battle between these two new bacteria have a thick capsule that makes them resistant to phagocytosis this is a nice illustration capsule makes the bacteria bigger and it also has specific chemical interactions with the macrophage the host on the other hand has a protein called c-reactive protein CRP this binds the Tyco ik acid in the outer membrane the outer peptidoglycan layer of the bacteria remember Tyco ik acids are stuck into that peptidoglycan if you don't remember go back and listen to me talking about it on one of the earlier bacterial lectures this binding of the protein to Tyco ik acid activates complement which is a host defense system that can then lyse the bacteria we can treat strep pneumoniae infections in fact there was a time when they were uniformly lethal but the development of penicillin shortly after World War one revolutionized the treatment of these infections and made people live who would otherwise die but guess what the overuse of penicillin and penicillin like antibiotics has selected for resistant bacteria and so now if you get pneumococcal infection it's much harder to treat resistance involves penicillin binding proteins that prevent the antibiotics from working we now have vaccines that can be used to prevent infections and there are two I want to tell you about one is a pneumococcal saccharide vaccine for adults so if you are an adult and you were never immunized you should get this so you don't develop pneumonia caused by this bacterium at an older age when your lung functions start to decrease this vaccine will protect you against 23 different serotypes there's also a vaccine for kids you should give it to them it's called the pneumococcal conjugate vaccine it contains 13 different serotypes of pneumococcal antigens linked to protein carriers so give it to your kids and they won't have to get the vaccine when they get older because they will be protected so today we have talked about two kinds of gram-positive cocci that cause a variety of skin and systemic infections the Staphylococcus and the streptococcus diagrammed here and after listening to all of this I hope that you'll know the structure and virulence of factors produced by both staphylococci and streptococcus I you'll be familiar with the pathogenesis and the epidemiology of diseases associated with Staphylococcus I and streptococcus I'd you should know which drugs can be used to treat staphylococcal and streptococcal infections and the problems associated with treatment and you should become acquainted with the available streptococcal vaccines thanks for listening and stay tuned to hear all about bacteria in your intestines hello and welcome to enteric bacterial diseases we're going to explore a few different kinds of bacteria that infect the intestinal tract and after you've listened to this lecture you'll know the structure and virulence factors produced by bacteria that cause enteric infections you'll be familiar with the pathogenesis and epidemiology of enteric bacterial diseases associated with Vibrio ecoli Shigella and salmonella and you should know how to treat these enteric bacterial infections first we're going to look at a condition called secretory or watery diarrhea which you and I have had for sure maybe not caused by bacteria could be viral but this is going to be different from diarrhea we talked about later which is bloody diarrhea all right secretory watery diarrhea and we're going to look at members of the Enterobacteriaceae II and the Vibrio naca they're both gram-negative rods two different kinds of bacteria one shown on the left the ecoli and the one on the right the vibrios these bacteria are transmitted to humans in contaminated food and water contaminated with what fecal material of course either human or from another animal so in the end it's all about keeping your food or water clean which we seem to have problems doing these bacteria that cause watery diarrhea adhere to the epithelial cells of the gastrointestinal tract we showed in a previous lecture a slide showing the structure of the wall of the gastrointestinal tract it's lined with epithelial cells which you can see at the bottom of this slide and the bacteria we're going to talk about sit on this surface of this epithelium they don't go in they don't invade they're not invasive they sit on the top and have their effects right there and they had he revived their pillow and those are composed of surface adhesions and again if you don't remember what PIR go back to the basic bacteria lecture what these bacteria do is they make toxins the toxins get into the epithelial cells lining the gut and they cause problems they reduce sodium absorption and they increase chloride secretion they disturb the homeostasis of sodium chloride balance and that leads to water coming out of the cells and there you go there's your watery diarrhea caused by toxins very easy to treat you don't need antibiotics you just drink lots of fluids presumably water or perhaps some water-based fluids with electrolytes would be fine but just need oral rehydration therapy to replace what you're losing otherwise you get dehydrated and you have more problems let's talk about Vibrio first Vibrio cholerae the cause of watery diarrhea this bacterium is never a member of the human microbiome it is not part of our normal flora it is a normal inhabitant of the environment in particular coastal estuaries waters they live in close association with phytoplankton in the waters and so they're living there and they're very happy to be living there so why do they infect us well sometimes we enter this ecosystem or the organisms contaminate our drinking water or food somehow they can get into our food or drinking water typically when sewage systems aren't working properly Vibrio can get into our water supply and then they infect us and cause problems cholera is the disease caused by Vibrio cholerae it is the paradigm for secretory diarrhea it is upon which everything is based our knowledge understanding this condition Vibrio cholerae encodes two toxins that are important for causing watery diarrhea once you ingest the bacteria they get into your small intestine they make cholera toxin which is shown on the right of the slide there CTX and it's composed of a subunit which is the effector part and the five B subunits we talked about this in a previous lecture and a toxin co-regulated pilas that means the other toxin the toxin co-regulated penis is made at the same time as the cholera toxin and this penis allows the cholera to adhere the surface of the mucosal epithelium which is shown in the diagram on the right so you have lib Rios which are curved bacteria with a flagellum they're making the answer the intestinal tract they make this penis to it here and they produce cholera toxin at the same time now what does cholera toxin do it binds to a receptor on the surface white via the B subunits it's internalized and the a subunit is released into the cytoplasm of the cell this a subunit causes an increase in intracellular cyclic a MP it raises the levels this causes the imbalance in sodium absorption so it inhibits sodium absorption increases chloride secretion as a consequence the cells trying to adjust they get rid of water bingo watery diarrhea okay so cholera toxin is what does this by messing up the sodium chloride balance there you get your watery diarrhea very simple straightforward effect now this watery diarrhea is a consequence of the toxin and what it is what it does of course it washes the cholera bacteria out of your intestine and that helps to spread the infection if you happen to be in a place where the sewage treatment isn't very good you will excrete cholera bacteria into the sewage and it will then infect someone else via contaminated food or water the challenge with cholera is to prevent dehydration we say the watery diarrhea associated with cholera is a prodigious diarrhea when you have cholera you constantly excrete watery diarrhea it's not like once an hour or once every two hours it's continuously prodigious and if you didn't take in water or electrolytes you would die of dehydration and many people do especially young kids who can't take an in and out fluids so preventing dehydration is how you treat this you don't use antibiotics you just give people lots and lots of fluids and you have to give them a lot because as soon as you give them a glass of water it comes right out and you gotta keep doing this over and over to prevent them from dying in some countries they've made a marvelous invention called a cholera bed they're shown here I probably don't have to describe them to you it is a bed covered with a sheet of plastic you lie on the bed you're sick with cholera there's a hole in the middle of the bed you just lie there with continuous watery diarrhea there's no point getting up and going to the toilet in a in a facility like this there are many many people with diarrhea they couldn't have enough toilets anyway but you would just sit on the toilet all day because you have constant diarrhea instead you lie in bed and the watery diarrhea comes out of you goes into this hole and underneath is a bucket that catches the watery diarrhea modern medicine cholera beds it's actually just a way to collect the diarrhea of course what you really need to do is give people oral rehydration therapy it's very effective and you might think well isn't that the solution well it's not always available people and there's so many people have cholera in a given region that may be economically depressed it's not easy to find therapy to give people in particular water or water with electrolytes in it so you have to give this to people and you have to make great efforts to get it and deliver it to people otherwise people die but if you supply oral rehydration therapy you save their lives now not every infection with Vibrio cholera is symptomatic not every infection causes watery diarrhea you may ingest some vibrios with contaminated water or food and you may be fine and you could be infected for a couple of weeks and be shedding the organism potentially infecting someone else that's called an asymptomatic infection this is exactly what happened in 2010 you may remember there was a big earthquake in Haiti the earthquake wrecked the sewage system and so it wrecked many things of course and the United Nations decided to bring in workers from other countries to help out which was a good thing they brought in some workers from Nepal it turns out these workers are a good fry of them had asymptomatic cholera they were shedding cholera in their feces so they went to Haiti and they defecated into a toilet but the sewage system was broken so their cholera contaminated the water supply people in Haiti drank this contaminated water it was a huge outbreak of cholera as if they needed that in the midst of the earthquake now they had cholera we didn't find this out in - until a bit after the incident occurred that it was caused by these individuals from Nepal of course they didn't do it on purpose but many people were very upset about this and they were mad at the United Nations but it wasn't their fault okay so that's Vibrio no antibiotics give people water and they shall survive let's now look at eco lie in terms of it's causing enteric disease coli as shirisha coli very famous bacteria is a member of the human gut microbiota most of the strains are a virulent all the strings that we have in us as long as they stay in the gut they're okay now occasionally ecoli escapes the gut and causes other infections you know the way we are built is not ideal we have our anus right next to our genitals so material comes out in feces it's easy to contaminate the genitals and this is what happens in many people they get urinary tract infections where ecoli escapes from the from the intestine and infects the urinary tract can go all the way up to the kidneys and even spread beyond that so these eco lies are just our normal floor which aren't in the right place in the urinary tract and elsewhere and they can cause serious infections we're not going to talk about these today but I want you to know that the e.coli within you can sometimes cause problems within you and those can spread to other people as well what I'm talking about today are e---coli that come from other sources either humans or animals that are special strains that now have the ability to cause enteric infections all right other eco life strains that's a picture of e.coli by the way there rods beautiful rods other you coli strains not from you from other people or other animals can be pathogenic so these are spread by fecal oral contamination this can happen during food preparation if a food preparer has this ecoli in them perhaps they have any a symptomatic enteric infection with the strain that they acquired from somewhere else they can contaminate the food and you will get it manure contamination is a big one cows have lots of e coli strains in them which don't hurt the cows at all but if they get into people they cause diarrhea and often cow manure contaminates food of various sorts so for example crops are often irrigated with grey water that isn't so clean it has cow manure in it and it contaminates the crops and they're not washed properly you eat them and you get infection so washing crops with contaminated water or just consumption of contaminated water that somehow contains manure from cows or even human feces again from people who are infected with these unusual strains of E coli so the first strain we'll talk about and there are several is called an taro toxigenic ecoli or eTech lots of abbreviations we're going to be hitting here will show you a table at the end so you can remember them all eTech causes travelers diarrhea why is it caused that you go to another country within a day or two you get diarrhea watery diarrhea after you've eaten some local food that's travelers diarrhea it's annoying but it happens it affects children and adults all over the world you've probably heard of it it's caused by etext strains of E coli these use membrillo or peel eye adhesions to bind to enterocytes in the small intestine very much like the Vibrio that we've talked about and these strains the e-text strains make to enterotoxin a natural toxin is simply a toxin produced by the bacteria that effects your enteric tract the e-text strains of E coli produce an L T enterotoxin this is very much like a cholera toxin it gets into the cell causes increased amounts of cyclic A&P and what does it do to sodium levels pumps it into the cell pumps out chloride there you go you can your watery diarrhea as the cell then pumps out water to try and compensate LT enterotoxin the other toxin is called s T this causes cyclic GMP accumulation in cells which also results in secretion of fluid and electrolytes contributing to the watery diarrhea so to Android toxins both of their effects is to cause a imbalance in the ion makeup of the cell and the cell excretes water and you get watery diarrhea eTech ecoli to enterotoxins these bacteria are not invasive they sit on the surface of your epithelial cells in your gut they attach to the gut surface by the pill eye and they sit there make toxins and you have diarrhea they don't go in they're not invasive it's an important distinction these are simply bacteria very much like the cholera Vibrio cholera sits on the surface they do not invade let's look at another type of e.coli these are entero pathogenic ecoli or Ipek it's hard to remember eTech Ipek now entró pathogenic these also cause watery diarrhea but these bacteria are slightly different they do not have fimbriae to attach they have other things they have no st and they have no LT toxins remember those were two toxins produced by the e-tec strains which were important for causing the watery diarrhea but the EPAct strains of E coli do not produce those toxins so how do they produce diarrhea these apex strains of E coli adhere to the intestinal cells via two proteins one is shown as a helical protein in the first panel of the illustration and the second is via and intamin adhesion which is the small blue box and these calls the bacteria to adhere very tightly to the epithelial surface and we think that binding changes the surface and that causes the diarrhea we call this adhesion and effacement and it's a deformation of the villi caused by bacterial attachment and that causes diarrhea not the elaboration of toxins as with the e-text strains all right so those are enteropathy genic ecoli the next strain that we'd like to talk about are called an Tarot aggregative ecoli or e AG EC these are strains only found in people and I mention this because these are frequently seen in AIDS patients so these kinds of diarrheal diseases are associated with immunosuppression and TRO aggregative ecoli have fimbriae as you can see in this picture which aggregate cells in culture and that's why they're called Antero aggregative strains they bind to the intestinal mucosa they cause watery diarrhea without fever they are non invasive as are the other strains they do produce a number of toxins one of them is hemolysis and they produce an ST andro toxin similar to that of the e-text strains the esti enterotoxins cause increase in cellular cyclic GMP and this results in ion imbalances leading to watery diarrhea okay so those bacteria the Vibrio and the various strains of E coli cause watery non-invasive diarrhea let's now turn to enteric bacteria that are invasive they go beyond the surface of the epithelial cells they invade the submucosal and they become systemic and they also cause cause bloody diarrhea which is also known as dysentery so when you have blood in your diarrhea it's no longer watery diarrhea it is dysentery the intestinal pathogens that do this structurally damaged the large intestine and they invade the mucosa and that damage and invasion leads to bloody diarrhea or dysentery so bloody diarrhea or dysentery 30 passages a day not as much as cholera but 30 a day is still a lot so it is stools with blood yuccas and pus in them that's the definition of that dysentery these are life-threatening infections they require treatment with antibiotics it's not sufficient to provide water rehydration because here the bacteria are in your bloodstream and you can have all the water in the world you're not going to get rid of those bacteria unless you take antibiotics so they need serious treatment and we're going to talk about two different genera of bacteria that cause bloody diarrhea and dysentery first the Shigella shown on the left here and again we're back to E coli but these are again different strains of E coli that cause invasive diarrhea so you see e coli can be very different depending on what genes it has the first is the entró hemorrhagic or a HEC strains of E coli and the second the entró invasive strains or yuck strains of E coli so the Shigella come in four species Shigella dysentery a Shigella Flexner i Shigella boy D and Shigella sanae and these are all capable of causing dysentery these bacteria are spread from person to person via contact or by contaminated food or water and you don't need a lot of these bacteria to cause an infection only a hundred or a thousand are enough so very minimal contamination of food for example or transmission of minimal numbers is enough to initiate an infection so you ingest these organisms they go to your intestine and they invade through EM cells now M cells you may remember from an earlier lecture about bacteria are the cells that are interspersed throughout the other epithelial cells and these cells are constantly sampling the lumen of the intestine to make sure there aren't any dangerous antigens there so they take up things very actively and pass them through to immune cells on the lower side of the intestinal wall many pathogens take advantage of M cells to enter the host and Shigella is one of them they bind to em cells and they get passage through the EM cell and then they're released onto the underlying space which is called the lamina propria in this process M cells are often full of macrophages that are they are sampling antigens they take up the Shigella in this case but the Shigella are not destroyed by the macrophage they escape the phagosome in the macrophage which has taken them up get outside and they can spread elsewhere but this transitory experience with the macrophage causes the release of cytokines from the macrophage that causes inflammation of course the cytokines recruit other cells to the infected area and all of this causes the symptom of infection these Shigella by the way which are shown as the the red oblong bacteria here can then invade epithelial cells from the bottom so they've come in through the EM cell they're in the lamina propria and now they go back into the epithelial cell from the bottom they ride the host cytoskeleton up to the surface again and now they're back on the surface of the epithelial cells and they can go through multiple cycles of reinfection and being brought to the top again eventually this destroys M cells as well as epithelial cells the cells come off so you end up having erosion of the gut wall or an Elser so this is a physical removal of cells there's a consequence of bacterial inflammation you have an ulcer and in the continent in the process of doing this many other immune cells have been trying to clear the infection including neutrophils major defense cells from any bacterial infections as we've mentioned before these cells die in the process and they accumulate in the stool and that's what provides the pus for the stool the presence of all these dead immune cells so the lesion in the wall the dying neutrophils that gives you the blood and the pus in the stool part of the dysentery one of the species of Shigella produces another toxin called chigi toxin and Thaksin has a specific effect in our cells it Cleaves the large ribosomal subunit the 60s subunit and that stops protein synthesis so that basically kills the cells and is partly responsible for the cells leaving their position in the epithelium and causing that ulcer you do need to take oral fluids to take care of a Shigella induced dysentery you don't need intravenous fluids you can just take these by mouth you don't need to be treated with antibiotics as these are not invasive organisms you can use antibiotics but there's a lot of resistance out there and they're not effective let's move to e coli one kind of e.coli enter oh hemorrhagic e.coli or a heck now these are strains of E coli that are frequently in the news so you may have heard of them a heck Accola that caused non febrile no fever bloody diarrhea and hemorrhagic colitis is the name of this syndrome when caused by a hex trains so how does this work these are strains of E coli that produced toxin they produce ash Eagle Ike toxin which we've heard about before can close eye on imbalances leading to water secretion and there are several names for these strains as a consequence besides ehekk they're also called Stech which means she go like toxin-producing e.coli or hu sec hemolytic uremic syndrome associated entró hemorrhagic E coli as we'll see that's one of the syndromes associated with infection or Vero's cytotoxin producing you call IV tech strains well these are the same name for a heck type strains they are often classified according to the O antigen here we're showing lipopolysaccharide which is a component of the outer membrane of these gram negatives you may remember this if not you can go back to one of the earlier lectures in which we talked about this in detail one of the components of LPS is the O antigen which you can see at the top there and the O antigen is how we categorize many of these strains and so for example you probably have heard of e.coli o157 h7 this is a strain that's caused many outbreaks of dysentery and it's often acquired from cows if you eat undercooked hamburger you can be infected with a no one57 strain the cows have this bacterium in their intestines it does not harm them whatsoever but if it gets to you somehow either via the meat the meat can easily been be contaminated with cow feces during the preparation if you don't cook it enough you don't kill the organism you will get infected you will get the the diarrheal disease from it you can also get it from contaminated water again if the water is contaminated with manure in some way by improper preparation you will get this disease oh one five seven is a specific kind of O antigen so now you know what this means the lipopolysaccharide those O antigens at the very top in the previous slide that's what is categorizing this as o157 and if you're interested the h7 is a flagella an antigen the flagellum is the molecule that propels these bacteria around to move this is one of the proteins of the flagellum the H protein so now you know that these a hex strains are categorized by lipopolysaccharide and flagellar antigens these bacteria may cause something called hemolytic uremic syndrome and this is accompanied by hemolytic anemia the red blood cells are licen so you become anemic you have not enough red blood cells thrombocytopenia and kidney failure these are all associated with these a HEC infections a very large outbreak of an e HEC strained occurred a number of years ago in Germany and these were caused by a slightly different strain a brand new one that hadn't been seen before Oh 104 h4 so now you know exactly what the oh and the H antigens are this caused a big outbreak in Germany of food borne disease and it was traced to contaminated vegetables was actually an e aggregate EC strain now we talked about the e ICI strains is causing diarrhea and AIDS patients somehow this AG EC strain acquired a gene for the sheikah toxin which causes the watery diarrhea producing this new strain oh 104 h4 it was present on vegetables probably via contamination with dirty water and it wasn't washed properly and if you eat uncooked vegetables and you know people do like to eat their carrots uncooked and even cucumbers and sprouts particularly sprouts are never cooked and so these are common ways to get this infection but this is an interesting case where the Higa toxin had been newly acquired by one of these other strains in the barrel these ehekk strains produce proteins that allow them to attach and efface like the e pack strains so some not all of them produce toxins this particular strain and the German outbreak had acquired in schita like toxin but most of the e HEC strains simply attach any face you face the surface of the villi and that causes the diarrhea the production of a seagull Ike toxin if it's present may be responsible for a cytokine response in the mucosa you can get profuse bleeding and this is caused by interaction of the cytokines that we produce with the sheikah toxins which damages the blood vessel and a major complication as I mentioned is this hemolytic uremic syndrome this is a combination of damage to small blood vessels if this happens in the kidney you have kidney problems and if you have extensive lysis of red blood cells the remaining pieces of the red blood cells get hung up in the kidney further complicating kidney function these strains can also invade the brain where it can cause thrombocytopenic purpura and the sheikah toxins are on phages and again the sheikah toxin originally seen in Shigella the causing the loss of water from the intestine these are on phages so they're mobile these toxins can spread from bacteria to bacteria and that's presumably why the e 104 german strain arose by infection with a phage that delivered the Shiga toxin gene at some point these toxins are take to cells and inhibit protein synthesis now let's move to Salmonella these are another strain of enteric bacteria that cause focal infection of the vascular endothelium may cause bloody diarrhea as do some of the e.coli strains these bacteria infect not just the gut but a variety of other organs as well they can infect the bones for example in patients with sickle cell disease causing osteomyelitis infections with Salmonella are associated with nausea vomiting and diarrhea and then another consequence with different strains is called typhoid fever in which we have systemic spread of the bacteria these Salmonella strains are common members of the microbiome of many animals for example chickens cows and reptiles pet turtles often have these strains of Salmonella in them the turtles are fine in fact all of these animals are not affected by their presence but there have been outbreaks of Salmonella disease and children caused by contamination from pet turtles you buy a pet turtle at a pet shop you bring it home and you have a salmonella infection eggs are often contaminated with salmonella and there have been foodborne outbreaks of infection from egg products typhoid fever another manifestation of salmonella infection is often transmitted from a human carrier it's going to involve transmission via food or water a very famous example of this kind of infection typhoid fever is typhoid mary she was a carrier of the bacterium she was not sick and she was involved in food preparation and infected many many people until it was discovered that she was the source of the infection so typhoid mary lived many years ago and the solution was to put her away in a room and not had her interact with anyone which is not really satisfactory of course but now we understand what's happening and we can take other measures to minimize transmission from the scarier individuals who still exist so as you might guess these infections are acquired by fecal oral contamination in the case of typhoid mary for example the bacteria she's excreting them if she doesn't have good hand hygiene she's going to contaminate food preparation the bacteria make their way to the intestine they penetrate the mucosal barrier they enter em cells as well as epithelial cells and they're carried through to the underlying tissues by endocytosis by endo siddik processes bacteria make their way to the lamina propria which is again that space underlying the epithelial sheet in the process sodium chloride has imbalances is introduced so that diarrhea results and the bacteria then spread from the underlying spaces to the bloodstream so this is not something that we see with the watery diarrhea strains to spread from the initial side of infection they're confined but these Salmonella strains can spread typically from the lamina propria the bacteria enter mesenteric lymph nodes and then from there enter the bloodstream where they can spread so these infections are associated with gastroenteritis and the production of cytokines and an influx of neutrophils which attempt to clear the infection and of course as the neutrophils die they're released into the stool which has pus in it typhoid fever is a kind of infection that involves dissemination of bacteria from the intestine using the mechanism that I just described but there are also non typhoid 'el systemic infections with salmonella that are caused by food acquired bacteria which go beyond the lamina propria in the intestine get into the bloodstream and spread to other tissues these are not considered infections of typhoid strains of Salmonella they are they are non typhoid --all so let's look at how typhoid causing strains survive and in fact so we take them up into the gut as you can see on the top there there's an incubation period shown by the dotted line where the bacteria invade the small intestine move to mezack tarik lymph nodes and then enter the lymph system they can replicate in macrophages in various organs so once they're in the blood they can spread to various organs they're taken up into the organs they can replicate in macrophages of the liver the spleen other lymph nodes this is an asymptomatic phase part of the incubation period then these bacteria are released from the phagocytes into the bloodstream this initiates a septicemia or a bacteremia and that can again spread the infection to other organs and that release is associated with high fever it's a typical sign of typhoid fever once the bacteria are in the blood for this second phase they can invade the gallbladder and from there they can go on and reinvade other tissues but the gallbladder is an important site because this is often a place where chronic infection is maintained from the gallbladder of course the bacteria can get out through the bile duct into the intestinal lumen and be shed or they can reinvade tissues cause ulceration of peyer's patches and the gut mucosa be released into the stool and can be present in the urine as well so there's a cycle here that you can see from the initial infection multiple releases into the bloodstream and other organs and then release and reinfection as well this gastroenteritis can be treated with antibiotics but the use of fluoroquinolones in treatment of this disease is controversial and if you read the literature you will see people who believe you should treat or you should not the systemic non typhoid infections non typhoid o meaning not Salmonella typhi these require antimicrobial therapy of course in all cases when there's diarrhea you also have to have oral rehydration therapy typhoid fever itself caused by salmonella typhi is very difficult to treat people who are carriers of the infection cannot be the bacteria cannot be eliminated with antibiotic treatment so they have to be very careful not to contaminate others with the bacteria in them so we've now gone through a series of back area of various types that cause intestinal infections let's summarize this so that you can see it all together and try and make sense of it and these these tables will be a good place to study this if you need to remember them so we've talked about watery diarrhea or secretory diarrhea this is again when you have a lot of watery diarrhea nope no blood no pus no tissue invasion the site of infection is typically the small intestine and examples are Vibrio cholerae and the e-tec APEC and e AG ec strains of E coli all of those can cause this this watery diarrhea dysentery there's much less volume and there's also blood mucus pus in the in the diarrhea and these bacteria can invade and move beyond the initial site this is typically in the large intestine and this can be caused by Shigella we there are also parasites that can cause this infection and if you're interested we can talk about that and in the parasite lecture we have hemorrhagic colitis caused by ehekk strains of E coli again copious liquid like diarrhea but this has blood in it although there are no cells no tissue invasion this happens in the large intestine and again bloody watery diarrhea copious diarrhea with blood or pus in it and tissue invasion this happens in the ileum and the colon and we talked about strains of Salmonella that can do this there are also other bacteria including capillo back there and your cine ax that can accomplish similar diseases so this is a summary of everything on one slide you can see the different etek a pecky AG ec strains the e HEC strains of E coli Vibrio Shigella and Salmonella and exactly what kinds of disease they're causing again we have looked at gram-negative rods in this lecture in terms of their effect on the enteric tract we looked at Vibrio cholera we've looked at URI Xie coli strains and salmonella and I hope after you've listened to this lecture you know the straw during virulence factors produced by bacteria that cause enteric infections you should be familiar with the pathogenesis and epidemiology of enteric bacterial diseases associated with Vibrio with e.coli Shigella and Salmonella and you should know how to treat these enteric bacterial infections thanks for listening and I hope you enjoyed learning all about various bacteria and I hope after you've listened to this lecture you know the structure and virulence factors produced by bacteria that cause enteric infections you should be familiar with the pathogenesis and epidemiology of enteric bacterial diseases associated with Vibrio with e.coli Shigella and salmonella and you should know how to treat these enteric bacterial infections thanks for listening and I hope you enjoyed learning all about various bacteria [Music] you

Channel: Lecturio Medical

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Keywords: Bacteria, Structure of Bacteria, Bacterial Infections, Microbiology Bacteria, microbiology bacteria lecture, microbiology bacteria classification, microbiology bacteria crash course, Microbiology, Microbiology USMLE

Id: YwdYf4Yd3DE

Length: 107min 24sec (6444 seconds)

Published: Wed Jan 02 2019