Fundamentals 11:00 - 12:00 Scribe: Hillary Carney

Fundamentals 11:00 - 12:00 Scribe: Hillary Carney

Friday, October 23, 2009 Proof: Nathan Krauss

Dr. Briles Bacterial Pathogenesis 2 Page 7 of 7

I.  Host controls extracellular bacteria growth [S27]

a.  We’re going to talk just a little bit about iron because iron has some nice examples for pathogenesis. We used to talk about the host sequestering iron to prevent the pathogens from getting it, but it’s become more and more obvious that the host sequesters free iron because iron generates free radicals which can damage tissues severely. We keep our iron held very tightly. If it’s going from one place to another it’s bound by transferrin. When it’s in red blood cells it’s bound by hemoglobin. These are the two places where most of the iron is.

b.  In the mucosal secretions, lactoferrin is produced, and lactoferrin is produced without iron (as is transferrin) and when it encounters iron it binds it.

c.  Transferrin is designed to give iron up, so it can take it from the liver world where red cells are being destroyed and take it back to hemopoietic tissues. Delivers it there so it can used to make more hemoglobin, so you don’t have to eat as much iron as you use to make hemoglobin because we’re recycling it all the time.

d.  When lactoferrin binds iron its in the mucosal tissues, and the stuff in the upper airways goes into the stomach, and some of that iron is probably available again because the lactoferrin gets degraded and destroyed and we absorb the iron. If it’s in the lower mucosal surfaces all of that iron it picks up is lost. It’s keeping iron from damaging us, and it’s keeping it away from pathogens because iron is an important cofactor for almost all pathogens. There are few pathogens that live in us, mennigicocci is one of the ones that have figured out how to do this, they make their enzymes with manganese instead of iron because they are tired of fighting with the host over the iron. But for most of them iron is really critical.

e.  When you have a fever this results in the production of more transferrin and this makes it much less likely there will be any free iron in the blood at all, so were binding it even tighter. When we do that we are making it much harder for the pathogen to get its iron and grow. Fever is probably doing a number of things that are helping your body, and one of those is sequestering iron. So when you take aspirin think about the fact that you’re feeling better but you might be sick a few more hours because you’re letting the bacteria grow more.

II.  Two types of pathogenic bacteria [S28]

a.  There are two types of pathogenic bacteria: extracellular bacteria and intracellular bacteria.

b.  Extracellular replicate outside of our cells.

c.  Intracellular replicate inside our cells.

i.  Because intracellular can replicate inside the cells they avoid the problems of dealing with phagocytes and all the antibacterial mechanisms that exist on the outside.

d.  Extracellular have had to develop defenses to protect themselves against phagocytes and against complement.

III.  Extracellular bacteria [S29]

a.  Primary players are:

i.  Antibodies, complement, phagocytes, and the pattern recognition receptors.

IV.  Intacellular bacteria [S30]

a.  Primary players are:

i.  CD4 T cells (TH1 branch), macrophages, CD8 T cells, NK cells, and all the cytokines that are involved in creating all that inflammation

ii.  It’s the intracellular bacteria that we are trying to kill when we make a cell mediated immune response.

iii.  When you get your smallpox vaccine your body thinks there are intracellular bacteria there. It’s confused because everything is dead that gets put in your arm, but that’s the response that gets stimulated.

V.  Viruses [S31]

a.  Protection against viruses is mediated by antibody, interferons, NK4 and CD8 T cells, and some complement helps the antibody a little but that allows it to result in the lysis of some of our cells that we talked about.

VI.  From the perspective of the pathogen [S33]

a.  Just looking for a warm damn place. Not really malicious.

VII.  Virulence Factors [S34]

a.  They have special properties that are called virulence factors. We’re going to be talking about what they do to get past our innate immune response well enough to grow and multiply.

VIII. Virulence Properties [S35]- Important slide

a.  Have to have ability to exploit a niche, and they all have some niche that they are evolutionarily designed for.

i.  Usually have to be able to adhere to host tissues in order to accomplish this.

b.  Have to be able to evade the host immune response, at least partially.

c.  Have to protect themselves from attack by antibody and compliment.

d.  Have to be able to, in some cases, invade into cells, and to get into cells that have to avoid getting killed by phagocytes.

e.  Have to be able to interfere with host immunity, and they have to be able to survive in these sites.

i.  Some of these are overlapping things

f.  They have to have a way of getting what they need to eat, and our body is working pretty hard to not to have a lot of extra food lying around to make it hard for pathogens to get any.

g.  Have to have mechanisms to get into host.

h.  Important slide. Pay attention to large bullets.

IX.  Finding a Niche [S36]

a.  These are examples of different niches that different bacteria have.

b.  Not going to quiz you on these.

c.  Slide is to give you the notion that bacteria have not all found different places, but they sure get into a lot of different places.

i.  One of the reasons for this is that if you have bacteria living in place A, and you’re mounting an immune response against it, poor bacteria in B that was living in there and wasn’t causing any trouble there gets pushed out. They are always tying to find some place where no one else is living and that gives them a spot where they are the only ones that are causing the inflammation.

d.  Streptococcus pneumoniae

i.  Colonizes the upper airways

e.  Streptococcus mutants

i. adheres to the teeth

f.  Helicobacter pylori

i.  Lives in mucus lining of the stomach, which is a pretty cool place to live because they’re within an environment that is acidic enough and they can deal with the acid, and the immune response doesn’t come out and do anything about it because our immune cells can’t deal with the acid. And nothing gets in there to compete with them, so once you get helicobacter you can have the same strain the rest of your life. It actually reduces the acid level a little, and it turns out that it causes ulcers. But if you get rid of it you have a higher chance of getting esophageal cancer because of reflux of the acid causes esophageal cancer and if your stomach has helicobacter in it that reduces the acid. If you’ve got an active ulcer you would want to get rid of it, but if the patient doesn’t have an active ulcer you leave it alone.

g.  Wisteria Salmonella survive inside of macrophages.

h.  Salmonella which causes typhoid

i.  Survive in the bile and infect liver and spleen

ii.  They can live in detergent , which means when you wash your hands to keep them clean you actually have to wash the salmonella off. Normally when you are washing your hands your washing off bacteria, but largely you are just killing them, which is why they say you should wash your hands for a minute to two minutes. Salmonella is not killed by this so you can still get salmonella from chicken and potato salad even if you wash your hands with soap.

iii.  E. coli.- colonizes the gut

1.  Adheres to surfaces of the bladder and ureter.

2.  Streptococci also colonizes the gut.

iv.  So they are living in our lower intestine. So if your have a baby and your colonized with group B streptococci, because it’s hard to keep everything clean, the baby has a chance of getting infected. When this happens is after the water breaks then a path is open through the birth canal. Group B can get in and infect the baby. If the water breaks and the baby is born fairly soon there’s not much of a problem, but if the water breaks and the baby isn’t born for hours and hours the baby has a good chance of getting really sick.

i.  Mycobacterium TB

i.  Grows inside of cells and grows slowly. Takes days to divide. Most bacteria divide in an hour. Whenever bacteria divide they release particles, and those parts are signals to the immune system that there is a problem. If those parts are coming out really really slowly the immune system never gets the message so they can hang around in people for a long time before much of a response occurs.

j.  HIV

i.  Has a particular niche that it has fallen into. It lives in CD4 T-cells. These are the cells that are responsible for orchestrating the antiviral response, so by killing off these cells it makes it easier for HIV to survive.

X.  Adherence by many pathogens is important because… [S37]

a.  Adherence keeps bacteria from being washed out by the mucus flow. It’s necessary for subsequent tissue and cellular invasion. If you want to be transmitted to the next host, usually we don’t transmit a bacteria by making a core of ourselves and giving it to someone else, they have to be on the mucosal surface to get out. Where ever their niche is they have to be able to get back to that mucosal surface and keeping it populated so they can get to the next person.

b.  Turns out that Streptococcus pneumoniae has two forms. It goes through a phase transition. One lives in the deeper tissue and hangs on, but it keeps populating the surface. This is the kid that sticks his finger in the next kid’s eye, and keeps transmitting the organism in the daycare. They have to hold onto the surface if they are going to be there to do that.

XI.  Critical adhesion targets [S38]

a.  Not going to go through all these. These are a lot of different molecules that pathogens have learned to hold onto. If they all held onto the same molecule we would have gotten smart and quit making that molecule, but they are always looking for things that are new that we haven’t tried to get rid of. Some of these are blood group antigens, so some people are more susceptible to certain things based on our genetic variations and what’s on the surface of our molecules. Example: Malaria binds to one of the blood group antigens.

XII.  Bacterial toxins [S39]

a.  Come in two forms:

i.  Exotoxins- secreted molecules that can kill, damage, or alter host cells. There are many of these but the big ones you think about are: Diphtheria toxin, cholera toxin, tetanus toxin.

1.  Diphtheria toxin causes swelling in tissues and kills our immune cells.

2.  Cholera toxin causes the diarrhea that allows it to spread to the next person.

3.  Tetanus toxin is really a mistake. It’s an organism that’s really not supposed to be living in us. It lives in the ground. It’s really trying to paralyze earthworms so that it won’t get digested as the dirt goes through the earthworm, but its paralytic ability also happens to work on us. So if we immunize ourselves with tetanus toxin so that we don’t get paralyzed. If we don’t get paralyzed our body doesn’t have any trouble getting rid of the organism. That’s why the vaccine only contains the toxin, because that’s all that’s needed.

4.  Diphtheria vaccine contains the diphtheria toxin. If you can keep the toxin from acting then the body has no problem getting rid of the organism.

ii.  Endotoxins- very old term, these are the same as lipopolysaccharides, which is LPS, the outer membrane of gram negative bacteria. These toxins were made by the pathogen to try to do something to help it out in the host. This is only a toxin because the host has learned that whenever LPS is around you better have inflammation because there is bacteria there and you want to get rid of them. LPS is toxic to us. If you inject someone with enough LPS they will die of shock because their body is trying to do all the things it would do to protect against a bacterial infection except those things are designed for the infection to be localized somewhere. When LPS is everywhere at once one of the things that happens when you have inflammation is that the blood runs into the tissue and so the blood vessels get real leaky and if that happens everywhere you go into shock. Your blood pressure falls. Your brain and heart don’t get enough oxygen and the lungs aren’t oxygenating the blood and you die from shock.

iii.  This is a severe medical problem especially in people who are debilitated (have cancer, are immunodeficient, or have sepsis with gram negative bacteria) and the physician comes in with an antibiotic that’s going to kill all those guys, and if he doesn’t kill them quickly that patient is going to die of sepsis. He kills all the bacteria, they fall apart and release their membranes as particles. Now you have millions of particles form each bacteria that have LPS, and the patient dies of shock. The physician thinks of this as a toxin, which is killing his patients, your body thinks of this as a molecule of a pathogen that it can recognize.

1.  If you take a mouse that can’t responds to LPS you can’t kill it with injecting LPS. But it turns out that all the gram negative bacteria infect that mouse much better now, because the main immune response doesn’t work so then they die of typhoid or something else that they wouldn’t normally die of.