BACTERIAL DISEASES CAUSED BY ENZYME SECRETION

Stahylococcus aureus (Chapter 14)
Streptococcal diseases (Chapter 15)

Staphylococcus aureus
This is a ubiquitous gram-positive organism that is literally riddled with toxins. Unfortunately, many strains are resistant to antibiotic therapies due to:

1) beta-lactamase producing plasmids
2) chromosomal-mediated drug resistances
3) tolerance to antibiotics
This is the first totally drug resistant bacterium

When these bacteria are inside tissues they elaborate various toxins/enzymes that facilitate its colonization

Enzymes
catalase - breaks down H2O2
coagulase - this clots blood and coats the bug with fibrin
hyaluronidase - spreading factor
staphylokinase - slowly dissolves clots
plus various other proteases, lipases etc

Exotoxins
alpha toxin - hemolysin, and disrupts smooth muscle function
beta toxin - degrades sphinomyelin (component of cell membranes)
leukocidin - kills PMNs, and allows intracellular growth
exfoliative toxin- this is nasty stuff and causes skin to peel off of the body. Especially bad for kids.
toxic shock syndrome toxin-1 - fever, shock, skin rash, and loss of skin

Enterotoxins
Enterotoxins A-F - about half of the strains produce enterotoxins. They bind to neural receptors in the gut that stimulate the Òvomit centerÓ. rapid emesis, nausea, diarrhea, cramps.

Other toxin producing organisms (generally act by killing host cells)
Bordetella pertussis - causative agent of whooping cough (Chapter 19)
Yersinea pestis - causative agent of the plague (Chapter 20)

Streptococcus pyogenes
These are pyogenic cocci (Ôpus makingÓ). These are ubiquitous gram-positive bacteria, with many pathogenic strains. Most strains are classified as A, B, or C, and they all elaborate polysaccharide capsules (84 types). In order to get these bacteria to grow on solid medium, blood products need to be incorporated into the medium. They are also facultative anaerobes.

The classification is based on hemolysis (digestion of blood), Lancefield groupings (i.e. how they type with respect to a specific antibody), types of capsular polysaccharide production, and biochemical testing. The major hemolytic strains (alpha and beta) are also divided into serogroups based on a PG-associated carbohydrate (these are the Lancefield groups).

There are many drug resistant strains (mediated by both plasmid and chromosomal drug resistance markers).

Many virulence factors are associated with these bugs:

1) M protein - this is a heat stable antiphagocytic hair-like extension that is associated with the cell wall. M protein is similar in structure to collagen, and there are many M serotypes (>80). Overall, the M serotypes fall into two groupings: class I and class II.
2) toxins and enzymes - when infectious the bacteria multiply in intracellular tissues where they elaborate these toxins/enzymes.
streptokinase - dissolves blood products
streptodornase - DNase hyaluronidase - (spreading factor) - degrades hyaluronic acid (component of membranes)
pyrogenic toxins A-C - (erythrogenic toxin) -causes a high fever and rash in scarlet fever
hemolysins

streptolysin O - inactivated by O2
streptolysin S - oxygen stable

Both digest blood products
diphosphopyridine nucleotidase - kills PMNs

Basically, the bug is providing itself with the necessary enzymes to establish an infection within tissues.

Diseases caused by Group A, beta-hemolytic S. pyogenes

1) eryspelas - skin infection
2) puerperal fever - endometritis
3) sepsis - blood poisoning
4) sore throat - nasopharyngitis ---> tonsilitis
5) scarlet fever - (pyrogenic toxin A-C) - fever, rash,
6) impetigo - skin infection
7) acute and sub-acute endocarditis - colonization of heart valves
8) streptococcal toxic shock syndrome - fever, rash, and shock (pyrogenic exotoxins A and B), 30% mortality rate.
9) necrotizing fasciitis - Òflesh eating bacteriumÓ Infection of the subcutaneous tissue causing destruction of fat and fascia.
10) rheumatoid arthritis - bacteria in joints leads to joint destruction and/or cross-reactive antibodies to joint tissue.

All the above are primary diseases that result from Strep infection. However, these can lead to immune-mediated sequelae

a) rheumatic fever - occurs 1-4 weeks following a respiratory infection. Caused by cross-reactive antibodies with myocardial tissue, or, more likely, due to the deposition of immune compexes.
b) glomerular nephritis - occurs 1-4 weeks following a skin infection, especially caused by M protein types 12, 4, 2, and 49. Here immune complexes are deposited in the glomerular basement membrane.

Antibiotics are still good for treating streptococcal infections with most strains still sensitive to penicillin and erythromycin. Infections can generally be prevented by good personal hygiene, isolation and early diagnosis.

Other diseases caused by streptococcci:

S. mutans - causative agent of dental caries. This is one of the most costly infectious diseases.
S. pneumoniae - differes from the other streptococci in that it is a diplococcus (as oppose to chains). This is the causative agent of bacterial pneumonia, which is the third leading cause of death in patients over the age of 60 years 9also a major cause of death with AIDS patients). Capsular polysaccharide is an absolute virulence factor here (over 100 serotypes).

BACTERIA THAT CAUSE DISEASE BY HIDING OUT

Salmonella diseases (Chapter 16)
Shigella dysenteriae (Chapter 16)
Camylobacter jejuni (Chapter 18)
Mycobacteria (Chapter 24)

Diseases caused by Salmonella ssp.

Typhoid fever is caused by Salmonella typhi. This is a rare infection in the US but very common around the world. Spread via the fecal/oral route, and generally occurs in epidemics when an individual brings it into a community. The bacterium is restricted to humans, and the severity and duration of the disease depend on how many bacteria are ingested, the virulence of the strain, and the relative health of the individual. Many infections are asymptomatic (typhoid Mary!). The bug grows in the gut and causes fever, headache, cramps and diarrhea. As they grow they invade mucosal cells which causes inflammation and pain (entercolitis). Most people recover. In other cases, the organism invades macrophages and can become septicemic. This causes shock - also the bug may invade literally any organ in the body causing abscesses and sometimes death in 10 to 15% of the time. Occasionally, the bug hides in the gall bladder and becomes latent. Here the patient has no symptoms but sheds infectious organisms for years.

Non-typhoidal fever
This is cause by S. typhimurium. Usually, there are between 20 and 30, 000 cases per year in the US. The organism resides in a variety of animals, especially fowl. Most cases arise due to improperly prepared chicken, turkey, and eggs. Incubation time is about 24 hours, and the bacteria invade gut mucosal cells. Causes severe diarrhea, nausea, and cramps and generally resolves itself quickly.

Dysentery
Caused by Shigella dysenteriae and is also transmitted by the fecal/oral route. Invades the gut epithelium and causes Òbloody diarrheaÓ. This is a severe disease with a 1-3 day incubation period. Inflammation of the gut causes the bleeding and a massive PMN infiltration. An exotoixin is also released that can penetrate into the central nervous system and may cause death. This is a very common disease in the Orient and the Third World.

Campylobacter jejuni - this is primarily a disease of animals that causes up to 2 million human cases of diarrhea per year. Once in man is spreads via the fecal/oral route. This is an increasing infection in humans and does its business by invading the gut epithelium.

Helicobacter pylori - this bug hides out in the stomach (very low pH). The bug is found in approximately 20-60% of adults in the US. The bacterium lives under the gastric mucosal lining, and produces urease to counteract the low pH of the stomach (this is the reason it can survive). The organism causes gastrisis, peptic and duodenal ulcers, and there appears to be a strong correlation of H. pylori infections with stomach cancer.

MYCOBACTERIA (Chapter 24)
There are two important infectious forms:
Mycobacterium tuberculosis - causes tuberculosis
Mycobacterium leprae - causes leprosy

Various mycobacteria species are found widely distributed throughout nature (infects humans, snakes, birds, fish, etc.). They have an unusual cell structure totally unlike either gram-poisitive or gram-negative bacteria. They are typical bacteria from the peptidoglycan layer inwards, however, on the outside they have a dense lipid coating that accounts for approximately 60% of the cell mass. This dense lipid layer is useful for the bug as it prevents the penetration into the bug of antibiotics, and also protects the bacterium from the immune system. It also slows down nutrient uptake, so consequently they grow very slowly.

Mycobacteria are not especially virulent, and usually only infect immune compromized people. An infection proceeds slowly and is accompanied by ÒwastingÓ. The common name is ÒconsumptionÓ (essentially the bug slowly consumes you). Also refered to as the Òwhite plagueÓ.

For TB to become epidemic, it requires a lot of immune compromized people living in close proximetry - this occurs in the inner city (where TB is on the rise) and increasingly with AIDS patients, who are very susceptible to secondary TB infections. The disease is transmitted by aerosol inhalation (i.e. infected people cough up sputum containing TB bugs, and people living in close proximetry breathe in this contaminated air). There is only one known virulence factor (cord factor) which causes the extracellular lipid to form Òcord-likeÓ chains or ropey structures. Virulence is not really well understood.

primary TB - here the bacteria gain access to the lung where they invade macrophages (sometimes they also get into the local lymph nodes). In either case, for healthy people the macrophages kill the bug and the infection generally stops here. secondary TB - this occurs if the person is debilitated in someway. For some reason, the organism in the lymph nodes or the macrophages canÕt be destroyed and the bodyÕs response is to surround the bug with tissue ---> tubercle. If the bacteria can be destroyed in the tubercle then the infection can terminate here. However, if they canÕt be killed, the center of the lesion becomes ÒcheeseyÓ and this is called a caseous lesion. In this state the bug can remain for dormant for years within the lung tissue. However, as the immune system of the host deteriorates over time the bug eventually escapes from the tubercle, resulting in recrudescent TB. This series of events (hiding/release) can go on for years. However, once the bug starts getting out of the enclosed tubercle, it can desseminate all over the body and infect other organs. Once you reach this stage death ensues quickly. Therefore, when the bugs are actively infecting the lung, they are residing intracellularily and are consequently hiding from the antibodies mediated responses. TB stimulates cellular or cell-mediated immunity probably due to its intracellualr location and its extensive lipid coat. 25% of TB sufferers elicit no Ab response. However, several of the lipid components are extremely immunogenic for effector T cells and TB stimulates a major delayed hypersensitivity reaction which the tubercle is a manifestation.

Delayed Hypersensitivity

TB stimulates cell-mediated immunity, because the lipids are extremely immunogenic for effector T-cells. Stimulates a delayed hypersensitivity reaction. The tubercle is a consequence of stimulating a delayed hypersensitivity and is also known as a granulomatous lesion. This is caused due to the effector T-cell response of CD4+ cells.

1) Circulating sensitized T-cells contact the antigen that is within the lung tissue (i.e. due to the bug residing within the tubercle for years the immune system is always being presented with TB-specific Ags which sensitize the immune system). Thus the T-cells are all primed up and ready to go.
2) When stimulated the T-cells elaborate chemokines which

a) attract PMNs, T-cells, and macrophages
b) induce T-cells and macrophages to divide
c) prevents macrophages from leaving the site
d) enhance phagocytic functions such as ingestion and intracellular killing

3) The macrophages and PMNs dump toxic lytic enzymes which damages normal tissue
4) Cells around the lesion compact which makes the tissue hard and results in inflammation.
5) If the antigen is not removed, the antigen (i.e the TB bug) becomes walled off in the granulomatous lesion.

Presenting delayed hypersensitivity is not a good sign for recovery. In fact, if you stimulate a major DH reaction the bug can leave the tubercle, which makes people normally non-infectious become highly infectious through coughing up TB bugs and spreading them by aerosol droplets.

Treatment: this is a hard disease to treat with antibiotics. The first one that was any good was streptomycin. Unfortunately, this antibiotic also causes deafness. Nowadays, TB patients are given long-term treatment with rifampin, ethambutol, and isoniazid. Unfortunately, many TB strains are becoming multiple drug resistant. People can be vaccinated against TB (done in Europe) however, not done in the US because i) the risk of a severe reaction to the vaccine exceeds the risk of disease, and ii) the medical establishment has a vested interest in maintaining the usefulness of the TB skin test for detecting infected people (vaccinated individuals are naturally skin test positive). However, many dollar bills involved in these decisions (vested interest of the pharmaceutical companies in providing the skin test is also involved).

 

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