General Pathology: Pathology of Infectious Diseases, Part Ipg. 1

Marc Vance

He tells the story of finding a case of Neisseria meningitidis recently in the hospital. Is it dangerous for the lab tech? No, because they have had the meningococcal vaccine, and were handling the organism properly. However, those who were caring for the patient probably should take antibiotic prophylaxis, probably ciprofloxacin.

Pyogenic bacteria. Here’s an abscess you can drain puss out of. We think of pyogenic bacteria as puss producing organisms. Abscesses and puss are the typical pathological lesions you see with these organisms. With strep throat, you get puss on the tonsils. The bacteria attach to the tissues that they are going to cause infection in, and then they invade. This stimulates neutrophils to come to phagocytize the bacteria. The neutrophils release enzymes to kill the bacteria that can also cause damage to tissues. And also the bacteria can release exotoxins which can further damage the tissue. That’s why you get the inflammatory reaction and necrosis associated with toxin mediated bacteria. This is typical for many different organisms.

Tissue penetration can occur in a lot of different ways. This child has an orbital cellulitis due to Haemophilus influenza. You see a big, swollen red eye. You can have the inflammation process that’s not necessarily a collection of puss, but also could be a diffuse suppuration. You see the redness, that’s a cellulitis.

Toxin production also aides in the penetration of tissue. This is necrotizing fasciitis, another disease caused by Group A Strep (flesh eating bacteria). This patient developed the flesh eating bacteria in the site of a skin biopsy and died two days later. The toxin producing Streptococci eat into the skin, causing a cellulitis. They spread through the fascial planes, causing thrombosis, infarction, and gangrene of the underlying tissues. If you get something like this on an extremity, you must amputate to save the patient’s life.

This tissue from the thigh where the infection occurred shows inflammatory cells and bacteria in the background. This strep spread throughout the person’s body and into every organ, killing the patient at twenty-three years old.

Many times when bacteria produce disease, there are very specific relationships between structures on the bacteria and cells in the host. Many bacteria are host specific, and even tissue specific in terms of the things the bacteria have that help them to attach. Mycoplasma pneumonia is a good example of this. The organism has a specialized attachment structure that allows it to attach to the respiratory epithelium, causing local damage and coughing. You end up coughing and coughing with this. It also stimulates the inflammatory response, and can cause pneumonia.

Many organisms don’t have to produce a lot of toxins to cause disease. The most common cause of community acquired pneumonia is Streptococcus pneumoniae. This is what you would see in the alveoli of someone with Pneumococcal pneumonia. You see the inflammatory reaction because of the neutrophil chemotaxis and increased vascular permeability which allows protein and fluid to seep into the alveoli. This forms an excellent culture fluid for the bacteria, and it’s why they grow and multiply, interfering with gaseous exchange. You can get significant disease that spills into the bloodstream even without significant exotoxins. Exotoxins are not always needed for significant disease.

Chronic infections such as Mycobacterium and Chlamydia trachomatis can occur when organisms live inside of cells. Remember the Chlamydia and Rickettsiae are obligate intracellular bacteria that always live inside host cells. This helps protect them from the immune system. It’s a virulence mechanism they have adapted by living inside host cells including phagocytes.

Some diseases might be caused by our own immune reaction. It’s not something that the bacteria is doing, it’s the reaction that our bodies have to the microorganism that can produce disease. Perhaps the best example of this is acute rheumatic fever caused by Streptococcus pyogenes. Following a sore throat with S. pyogenes, you get antibodies produced against the M protein of the strep. These antibodies that are produced can cross-react with antigens in the heart, causing damage to the heart. The mitral valve is shown damaged and calcified through dystrophic calcification. Ultimately the valve can fail by mitral valve stenosis. You are also at risk of getting subsequent bacterial endocarditis infections on the heart valves because they have been damaged.

The other example of autoimmune disease associated with Strep pyogenes is acute glomerular nephritis. Here you have a type III immune complex development in the bloodstream which precipitates in the kidneys. This follows a strep infection. That’s two examples of how strep can produce an autoimmune reaction as a mechanism of disease.

It’s important to review again the differences between exotoxins and endotoxins. Remember the endotoxins are thought to be only part of Gram (-) organisms because they are a part of the cell wall (LPS). The exotoxins are proteins that are secreted by the bacteria, and they occur in the cytoplasm. The LPS is associated with the outer membrane of the cell envelope of gram (-) organisms. Endotoxin is released when dead organisms are lysed, while exotoxins are released by living organisms.

There are a lot of different actions of exotoxins. A few you should be familiar with are in your book and learning objectives. The diphtheria toxin interferes with protein synthesis. The cholera toxin (from Vibrio cholera) is a diarrheal disease. The main symptom of cholera toxin is intense diarrhea. There’s a bacteriophage encoded toxin that is released when the organism is in the bowel that stimulates cyclic AMP through a complex reaction which ultimately causes the secretion of bicarbonate and chloride into the bowel. Large amounts of fluid follow the chloride and bicarbonate. Severe dehydration is a result, and it can be fatal in young children.

Clostridium tetani produces lockjaw because the tetanus toxin interferes with the release of inhibitory neurotransmitters which balance the neurons, causing them to always be in a hyper-excited state.

Remember endotoxins have a complex array of effects. Remember, exotoxins have specific mechanisms and reactions at specific cells. Endotoxin is much more complex. It is composed of lipopolysaccharide, and it does a lot of things. Endotoxin really accounts for what we call septic shock.

One of the most common reasons that people die in the hospital is septic shock. This is because they get a gram (-) bloodstream infection. This can occur in many people. Most acquire the infection while in the hospital as a consequence of underlying disease. For example, cancer patients often die from infection because they are weak from their malignant disease. The patient has poor appetite and poor resistant to infection. In this immune-suppressed state, along with surgical treatments for tumors, patients are at great risk for infection. The immediate cause of death for most cancer patients is infection acquired because of their cancer.

This is an example here of what endotoxin can do and why it’s so severe when you have bacteria that invade your bloodstream. You get damage to the endothelial cells of the bloodstream by the endotoxin. This stimulates the coagulation cascade and disseminated intravascular coagulation. The endotoxin also stimulates macrophage activity and IL-1. This in conjunction with the hypothalamus is why you get fever. Of course you get all these other things such as complement activation and increased vascular permeability and other things that can lead to hypotension and shock. There’s a whole gamut of reactions that can occur because of these complex interrelationships between the endotoxin and the entire body.

This is an example of a patient that had gangrene and DIC due to the endotoxic effects of Meningococcal sepsis. Remember that the endotoxin is the most important virulence factor of Neisseria meningitidis.

Another concept that you may have heard of in immunology is that of bacterial superantigens (SAGs). Superantigens can be things like bacterial toxins that actually bypass the normal antigen presentation because they bind Class II MHCs on antigen presenting cells and T cell antigen receptors. They stimulate “cytokine storms.” They activate T-cells at many orders of magnitude higher than normal. This is what causes the shock in toxic shock syndrome. Remember that toxic shock syndrome is associated with a rash and multi-organ failure and can be caused by Staphylococcus aureus as well as Streptococcus pyogenes. The toxic shock toxin that these organisms produce is considered a superantigen and potent stimulator of T-cells. A vigorous outpouring of cytokines is observed.

Let’s move on into viruses. You haven’t studied viruses so far, so this will be an introduction. We have a number of case studies of viral diseases available in the IP labs that are available. There are four different IP labs that correspond to the lecture that we did on Tuesday and today. Virology will be presented after the micro exam next week. Today is just an overview.

Viruses are much different from bacteria. The simplest viruses are simply nucleic acid surrounded by a protein coat. Some of them are more complex and have various envelopes, but they will only have one type of nucleic acid, either DNA or RNA. It could be either single or double stranded. The RNA viruses must undergo a complex mechanism for replication. The main thing you have to understand is that viruses, like Chlamydia and Rickettsiae, are obligate intracellular parasites. They depend on the host cells metabolic machinery and amino acids and everything else in order to assemble new virions. Viruses are the simplest form of life, and of course cannot be cultured in a laboratory like bacteria. You have to grow them inside other cells for diagnosis.

Common among all viruses is the fact that they must find the cell they are going to invade. Many viruses are tropic for specific types of cells. The HIV virus must infect T-cells. You can look at different types of viruses, and they may go to only a certain cell, or other viruses can infect a multitude of cells. But all viruses must get inside the cell to replicate.

They must have a form of attachment. They must have a form of penetration. And they must “undress themselves” once they get inside the cells. They have to uncoat their nucleic acid, remove their capsid, and then replicate their nucleic acid and then synthesize new virus proteins that will make new capsids. Then all those things have to be put back together. They must then release from the host cell. Here you see HIV budding off of the host cell. Some other viruses grow to large numbers inside the host cell until the host cell simply bursts, releasing the viruses.

The influenza virus is one of the best studied viruses. It has two main surface antigens. It has the hemagglutinin (the red spikes) and the neuraminidase (blue spikes). The hemagglutinin allows the virus to bind to the respiratory epithelium. Then the neuraminidase actually facilitates the release of the virus after it’s replicated from the infected cell. These two structures on the surface of the influenza virus are very immunogenic. They are the basis for the influenza vaccine.

As health care people, we should get the flu vaccine. For our sake, and the sake of our patients, we don’t need to get the flu.

The influenza virus exhibits antigenic drift, making vaccine production difficult. There are different combinations of H and N antigens that are constantly mutating. Every year, the strains change, and a new flu vaccine must be guessed and produced. Sometimes the vaccine is very good, other times it is not as good. The vaccine is based on the H and N antigens.

A treatment for the flu is the new neuraminidase inhibitors. These drugs block the activity of neuraminidase, treating the disease.

Minor changes in the antigens are called “antigenic drifts.” Major changes are caused “antigenic shifts.” The flu can be pandemic. In addition, the flu might not kill you, but it can leave you wide open to a bacterial infection because of the damage done to the lower respiratory tract. So pneumonia often ends up killing those with the flu.

Let’s talk about some ways that viruses kill host cells. Polio virus is a very simple RNA virus. It’s a virus that has a particular tropic effect to the motor neurons in the nervous system. It attacks the motor neurons in the spinal column, damages them, and that’s why you get paralysis. It actually inhibits DNA and protein synthesis when it gets inside of neurons, and the cells die.

Some of the other ways that viruses produce damage is that they insert into the host cell membrane. This can promote cell fusion, as seen in the measles. With measles, you can get giant cells because of the influence of the virus causing the cells to fuse. The influenza virus simply invades the epithelial cells, and kills them when the virus is released after replication.

Hepatitis B virus causes significant liver disease. When a hepatitis virus invades a liver cell, it will express the viral proteins on the cell surface. What does that do? It tells the host immune system that the virus is present. The collateral effect of this is that the host immune cells go and attack all the infected cells in order to get to the virus. So the immune response is what actually kills the liver cells, causing much of the liver damage in hepatitis. The greater the immune response, the greater the damage.

HIV damages the host immune cells. The reason you get sick with HIV is that you get an opportunistic infection with another virus or fungus because all of your T-cells are damaged by the HIV. So you get Cryptococcus or Pneumocystis that are such a big problem for HIV patients. This is not as much of a problem as it was in the past because we have better drugs that stimulate the immune system. Early on in the history of HIV, patients died quickly because their T-cell counts went so low.

Back to polio. It is an excellent disease in terms of understanding mechanisms because a lot is known about it. When the polio virus invades the neurons of the spinal cord, the neurons die. If you lose the innervations to the muscles of the legs, those muscles atrophy. The paralysis and the atrophic limbs associated with polio are a result of the loss of muscle cells due to the loss of innervations because of the polio virus.

You can also get slow viral infections. One of the most important reasons for the measles vaccine was not because of the rash and fever of young kids, but the fact that about 1% of everyone that gets the measles gets a reactivated virus months later. This reactivated virus is called subacute sclerosing panencephalitis (SSPE). This is almost always fatal. So 1% of all people who get the measles die, and a big reason that the measles vaccine was developed.

Human papilloma virus causes cell proliferation and cervical neoplasia. There’s a lot of publicity about the Gardasil vaccine that prevents teenage girls from getting cervical cancer due to papilloma virus. There are a number of other viruses that cause neoplasia. The more we learn about viruses and cancer, the more we find that infections are a cause of many cancers. There’s a table in the textbook about various neoplastic viruses. We know hepatitis virus is often associated with liver cancer. Burkett’s lymphoma is associated with Epstein Barr virus. Kaposi’s sarcoma is associated with herpes virus.

This is what measles rash looks like and these are the giant cells that you get as a result of measles virus.

The host response to viral infection is somewhat variable, but there are a few generalities that you can make. The inflammation that you get in response to a viral infection is more typically monocytes and lymphocytes as opposed to neutrophils, which you see with bacterial infection. Like many bacterial infections, you get antibodies formed naturally as a consequence of the infection. These antibodies help block attachment, penetration, and uncoating. Of course this is the basis for many viral vaccines that we have. The vaccines will block one or more of the steps of the viral replication process.

Something else that occurs in viral infections is interferon production. Interferons are naturally occurring substances that inhibit the translation of viral proteins and prevent replication. They also enhance T-cell and natural killer cell activity. Interestingly, interferons can now be made synthetically to help bolster the immune system in viral infections (particularly in Hepatitis C).