Fundamentals II: 10:00 - 11:00Scribe: Matthew Davis

Tuesday, November 17, 2009Proof: Jennifer Grimes

Dr. WaitesPathology of Infectious DiseasesPage1 of 8

Introduction [S1]:
Learning Objectives [S2]
We are going to be talking to you about the perspective of the host and the diseases that the microorganisms cause, giving examples of specific diseases. You’ll note that we will do part of the lecture today and finish it tomorrow. There are 4 IP labs that go with these series of lectures. There is one on bacterial, fungal, viral, and parasitic diseases and we will attempt today to do bacterial and viral diseases and tomorrow we will do parasitic and fungal diseases.
You have an outline of the material here, we will go through and talk about infectious diseases. We are going to review the host defenses and pathological responses to infections. This goes back to immunology as well as the pathogenic microbiology that was studied last week.
We will talk about mechanisms of various diseases and use specific microbes as examples. We aren’t gonna go back and talk about all infectious disease but we will pick some mechanisms of diseases and use a common type of microorganism to illustrate the example of the diseases.
We will talk about how infectious diseases can be diagnosed and this relates to some of the things you saw in the microbiology lab already but it never hurts to have a little repetition and to put things into the proper conceptual framework.

Top 10 Causes of Death [S3]
What do people die from? It depends on where you live. If you look here for example in the US: Heart disease, cancer, cerebrovascular disease, Chronic obstructive pulmonary disease, injuries, diabetes, and then you get down here influenza and pneumonia, alzheimer’s disease, kidney disease and sepsis. Out of the top 10 there are two of them that are definitely infectious diseases and you can see indirectly in some of these other infections, if you say someone dies of cancer, well cancer is the underlying disease but what do they die from? In many cases they die from infections because their body is weakened and don’t have proper immune function anymore because of the cancer or the treatment they are taking so septic infections are very common cause of death in people with cancer. People with diabetes are prone to have lots of infections so you may see infections there. COPD, underlying infections in the lung is a common cause of death in someone with underlying disease, so you see indirectly infectious disease can play a role in some of these other things.
If you look worldwide infectious diseases are even more important. These are places where you include the developing countries that don’t have clean water or sanitation or nutrition and there are also tropical diseases that are much more common in other places of the world than here. If you look at the top 10 disease there you still see heart disease, cerebrovascular disease being important but just a general category of lower respiratory infection, HIV and Aids, COPD, parinatal infections, diarrheal disease most of which are infectious, Tb, injuries, and cancer. You see several components of infectious disease world wide. The stuff we are talking about today is very important in terms of causing morbidity as well as mortality

Host Resistance to Infection [S4]
What protects us from infections? You’ve been learning about the innate and adaptive immune system. There are many genetic aspects of things that protect us from infections. The resistance to infections is the combination of lots of things. There are all kinds of immunodeficiency and problems with our immune system that we learned about when you learned about the immune system. Our anatomy and physiology, the way our body was designed by our creator, protects us in many ways from infections and there are a lot of examples of what our anatomy and physiology does to protect us if we have things intact.
Immunocompetence relates back to the anatomy and physiology and genetics, if you mess up things here it can affect your overall ability to fight infection. And certain circulatory and ventilatory statuses are important as well. If someone for example gets in a fire and they inhale smoke and the smoke can damage the epithelium of your lung and so that will cause damage to the mucosal immune system, it will cause damage to the epithelium and allow infections to get inside through the airway epithelium that might not have been able to get there otherwise. So these two statuses make a difference to how well you can fight infections and of course underlying diseases, like cancer and diabetes, there are all different situations that put you at risk for infections

Natural Barriers to Infection [S5]
When you think about our natural anatomy and physiology, the natural barriers we have to infections, well your skin is your largest organ and is the most important thing to protect us against infection. You have been learning already about some example of microorganisms that can penetrate intact skin like the treponema or syphilis spirochetes, some of the parasites are other examples. Over all intact skins protect you against many microorganism but if you get a wound were the skin barrier is no longer there it allows microorganisms easy access to get into the body and cause infections.
In your mouth, lysozyme and saliva. Lysozyme helps to lyse gram + bacteria as part of the non-specific immune response.
In the GI tract we have normal flora that competes for space in our epithelium in our GI tract. Say you give someone a course of antibiotics for infections that can upset the normal flora in the GI tract, that is when you get the example of hospital acquired diarrhea, clostridium deficile is one of the anaerobic bacteria you learned about. Most of the epithelium in your large bowel is occupied by your normal flora. If your antibiotics kill off your normal flora than pathogens like clostridium wake up and realize there is more room for me and they start multiplying and making toxin and you get this toxin associated diarrhea.
The low pH of the stomach keeps most people out. But helicobacter makes urease, which raises the pH of the stomach in areas where it lives. It raises the pH of the stomach by its urease splitting urea and producing ammonia so it creates a niche for itself so it can live at a pH of 2 in a little microenvironment where it is buffering the pH by its urease activity. So that is a virulent factor that allows it to live in what would be an inhospitable environment for other organisms.
Of course in the respiratory tract we have mucociliary ladder, we have our cough reflex, we have macrophages that take up things that we inhale. If you do anything to mess these up than you get infections.
The urinary tract is very important. The fact that we urinate so many times a day it washes bacteria out that would otherwise be able to gain access into the lower urinary tract especially in women whose urethra is short. The bacteria have to get in there and attach and multiply to produce disease but if you urinate several times a day and empty the bladder completely very few bacteria remain. If you are a diabetic and you have a neuropathy and don’t empty your bladder completely or say you have a spinal cord injury and have lost voluntary control of your bladder and don’t empty it properly, you get bacterial infection because the bacteria that would normally be washed out with the urine are able to survive there and cause UTI there.
We talked about the vascular system there. You put an IV catheter in someones arm you have entered the bloodstream with a foreign object so bacteria that can attach to plastic or that can colonize IV catheters can go under the skin and into the blood stream and you get bacteremia otherwise they would not be able to get there. If you put an indo-tracheal tube in someone’s trachea to help them breath you bypass the mucociliary apparatus in the upper respiratory tract. If you put a urinary catheter in the bladder to drain the urine, you are bypassing the normal epithelium in the urinary tract.
All of these things you do will help bypass some of the normal immune system and barriers we have to infections and allow infections that would not otherwise occur to take place. Those are all things you think about when you think why does someone get that infection. It is normally because you have broken down a barrier. For example we hear a lot about influenza because we have this swine flu going around and we think about the pandemic flu that we had in 1918, well why did people die from that pandemic? There were two reasons, one was no one had natural immunity to it because the flu virus hadn’t been around before and secondly, when the flu virus comes in a destroys the epithelium in your lung and your air way is there it allows seriously more virulent bacterial pathogens such as the streptococci to come in and invade the respiratory epithelium so the reason people died in 1918 of the pandemic flu was group A strep pneumonia because the strep was able to get into the lung more efficiently because the flu virus had paved the way by tearing down the epithelial barriers there. That is why one microbe can assist another in causing disease.

Sources of Systemic Infection [S6]
So sources of systemic infections. Burns, if you do dental work and do tooth extractions you’ve allowed bacteria access to the blood stream. You stir up stuff and allow bacteria direct access to the blood stream because you remember the arteries and the veins in the gums there. You stir up things and bacteria may gain access to the blood stream and cause serious infections.
We won’t go through all of these things but it is easy to see how things that you do and procedures that you do and things that you mess up the natural barriers to infections and you get into trouble.

Host-Parasite Relationship [S7]
So lets talk about what happens when you do get into trouble, like you have already breached a natural barrier there. We have a very delicate host-parasite relationship. Our bodies are full of microorganism and in most cases when things are going right with our immune system and when our natural barrier to infections is in place the bacteria are kept in there place and aren’t causing any trouble. It is when they get out of the places that they normally inhabit or if they start growing to larger amounts, and I’m talking bout bacteria, viruses, fungi the whole group of microorganisms, its only when its normal relationship is altered or a new guy comes in from the environment, a new pathogen that you start having trouble.
You can really talk about the host-parasite relationship in terms of virulence. This is the ability of a microorganism to produce a lesion and the infectivity is the ability to be transmitted and established. The overall pathogenecity or disease causing aspect of the microbe is the sum of the virulence and its infectivity
For example a very successful microorganism is the measles virus. Presumably all of you got the measles vaccine when you were toddlers because you have to have it to get into public schools in Alabama. Measles is a very contagious disease. Now if I had an active case of the measles, it is spread by droplets, the very fact that I am standing here talking t you I am aerosolizing the measles virus if I had the virus. It is a very infectious virus. The fact that we are here in a room and if we closed the door and I got up close and started talking, the likelihood if you didn’t have the measles virus would be that you would get the measles. That is why it spread through schools. Before the vaccine, everybody got the measles sometime in there life because it had a high pathogenicity, even in a normal host if you get it it’s going to cause disease, and it has a high infectivity because it is easily spread
Now you could take another organism, a childhood organism, the mumps. The mumps virus is not nearly as contagious as the measles virus. So the mumps virus, if you get it you will get sick you get the paratitis but it doesn’t spread as easily. It has lower infectivity so not everyone got the mumps before the mumps vaccine. The measles is just naturally an agent that spreads easily.

Infection vs. Colonization [S8]
Another term is infectious vs. colonization. We use the term infectious to indicate the invasion of the body by a pathogenic microorganism and reaction of tissue to its presence and toxins. If you have colonization, that means you have the microorganisms. We are colonized by hundreds of different species of bacteria in our GI tract, mouth, and upper respiratory tract. They don’t usually cause trouble because they are normal flora. We are colonized by them but not infected by them if we don’t have a reaction of our body, an inflammatory reaction or immune system to them. These organisms that are part of our normal flora can cause infections but only when they get to be too many or get to be somewhere they shouldn’t be and you have a reaction of the body to it so be careful when you use the term infection because that implies an abnormal process the body is reacting to.

Exogenous vs. Endogenous Infection [S9]
We also need to classify infections by where they come from. We can think of the exogenous infections as those you catch from something or someone versus the endogenous infections which is the activation of these bacteria that may already be present in our body and we don’t have to catch it from anybody. These are the ones we will often refer to as opportunistic. They cause trouble only when something has happened to change the relationship of the host and its microorganism. For example, stress, radiations, treatment with antibiotics that affects the normal flora, steroids, chemotherapy that blunts the bodies natural immune system, trauma that would cause bacterial organism to get from one part of the body to somewhere else if you get a gun shot wound in the abdomen that pierces the GI it allows the contents of the GI tract including the bacteria to get into the perineal cavity where it should be sterile so you get peritonitis infection and underlying diseases there so all of these things can cause activation of endogenous infections.

Extracellular Pathogens [S10]
We can also classify bacteria as being extracellular or intracellular. We talked about different microorganisms and I gave you characteristics and I told they were intracellular bacteria or extracellular bacteria. Well, the way these organisms produce disease that have relationship with the host is very different.
Extracellular bacteria and pathogens have to resist phagocytosis. Once they are eaten by the host cell they die, because they don’t have a mechanism to prevent being killed by the phagocytes (neutrophils and macrophages). They have to find ways to avoid phagocytes. They do this in a lot of different ways. Staph aureus can produce leukocydin which are substances that kill white blood cells. They may produce capsules which help protect them from phagocytes, they cover up there antigens. This is Cryptococcus, it is an encapsulated yeast so fungi as well as bacteria can have capsule. You can also keep the immune system guessing by having different serotypes like strep pneumoniae which causes pneumococcal pneumonia, lobar pneumonia. It has lots of different serotypes so you can have an infection with one and you have antibodies that can opsinize that one so you aren’t likely to get an infection with that strain again but you can get a different serotype that can come along and make you sick. That is the basis for the vaccine we have, it stimulates your immune system to make antibodies against lots of the different serotpyes so when one comes along you are able to opsinize it and help phagocytize it

Facultative Intracellular Pathogens [S11]
Then you’ve got your facultative intracellular pathogens. We say facultative, meaning not obligate, we have to distinguish those from the Chlamydia and rickettsia the ones that have to live inside host cells. These are the bacteria that have adapted to being eaten by the host cells but can still go on ahead and do there business even inside of the host cell
Here is legionella inside a host cell. Legionella is the agent of pneumonia that lives inside of macrophages. Most of these organisms don’t have capsules because they don’t care if they are pagocytized or not because they can live inside of the phagocytes. They often don’t produce toxin because they exert there illnesses by the fact that they damage cells that they are inside of and spread from one part of the body to another
They have lots of different ways they can keep from being killed after they are ingested by a host cell.