Give an account of the pathogenic mechanisms employed by microbes in the causation of disease. How does the host’s immune system attempt to overcome these pathogenic mechanisms?

Outline:
•	Pathogenic mechanisms:
- direct cytocidal effect: polio, HIV, parvovirus, plasmodium
- adherence to cell surface: staphylococcus epidermidis, neisseria gonorrhoeae
- damage to epithelium lining: respiratory virus, rotaviruses.
- invasiveness: streptococcus pyogenes, clostridium perfringens.
- depletion of nutrients: giardia intestinalis, taenia saginata, ascaris lumbricoides
- presence in body structures: echinococcus granulosus, strongyloides, toxocara
- chronic inflammation: mycobacteria, hepatitis B, schistosoma
- toxin production: clostridia, staphylococci, endotoxin of gram-negative bacteria
- immune-mediated: dengue, streptococcus pyogenes, hepatitis B
- carcinogenic: HPV, Epstein-Barr, hepatitis B, clonorchis sinensis, helicobacter
•	Immune defense responses:
- humoral
- cell-mediated

Suggested Answer:

	Various pathogenic mechanisms are employed by microbes in the causation of disease. Microbe infection does not necessarily cause disease. The manifestation of disease depends on the virulence of the microbe, the quantity of microbes in the body as well as host susceptibility. As a consequence of the wide variation in disease-causing mechanisms, many different immune defense responses have evolved to deal with them and this also accounts for the many antimicrobial agents present in the market today.

	Cytocidal microbes kill the cells in which they replicate – the resulting cell damage is known as the cytopathic effect of the virus. This change in the appearance of the infected cell usually begins with a rounding and darkening of the cell and culminates in either lysis or giant cell formation. Poliovirus causes selective paralysis of the lower limbs by replicating in and destroying motor neurons in the anterior horn of the spinal horn. The human-immunodeficiency virus mediates its immunosuppressive effects partly by killing the CD4 helper T cells in which they reside. As the disease progresses, CD4 T cells gradually decline in number and function till patients have too few CD4 cells left to mount an effective defense against opportunistic microbial infections which soon overrun the body. The parvovirus targets human progenitor cells, causing lysis and aplastic crisis in children with chronic hemolytic anemia. The protozoa plasmodium lyses red blood cells too, leading to the characteristic symptoms of malaria.

	Certain bacteria have specialized structures, e.g. pili, or produce substances, e.g. capsules or glycocalyces, that allow them to adhere to the surface of human cells, thereby enhancing their ability to cause disease. The pili of Neisseria gonorrhoeae and Escherichia coli mediate the attachment of organisms to the urinary tract epithelium, resulting in inflammation of the urinary tract and genitals. The glycocalyx of Staphylococcus epidermidis and certain viridans streptococci allows the organisms to adhere strongly to the endothelium of heart valves, enabling them to cause infections of intravenous catheters and prosthetic implants such as heart valves.

	Some microbes cause disease by causing damage to the epithelial mucosal lining with secondary complications. Respiratory viruses, such as influenza, respiratory syncytial virus and rhinoviruses invade and cause necrosis of the respiratory epithelial lining. The destruction of ciliated epithelium increases the susceptibility of the respiratory tract to secondary bacterial infection, allowing pneumococci and other bacteria to invade the lungs and cause secondary bacteria pneumonia. Rhinoviruses and respiratory syncytial virus damage the mucosa of the nasopharynx and sinuses, predisposing to bacterial superinfection leading to purulent rhinitis, pharnyngitis, sinusitis, and otitis media. The principal virus causing diarrhea in children is rotavirus. Rotaviruses infect cells at the tip of the villus and cause marked shortening and occasional fusion of adjacent villi so that the absorptive surface of the intestine is reduced, resulting in fluid accumulation in the lumen of the gut and diarrhea. As the virus destroys the absorptive cells there is loss of those enzymes responsible for the digestion of disaccharides. This leads to loss of sodium, potassium, chloride, bicarbonate and water, and the eventual development of acidosis. Entamoeba histolytica invades the colonic epithelium and secrete enzymes that cause localized necrosis, causing dysentery. 

	A mechanism by which bacteria cause disease is invasion of tissue followed by inflammation. Several enzymes secreted by invasive bacteria play a role in pathogenesis. Streptococcus pyogenes secretes collagenase and hyaluronidase, which degrade collagen and hyaluroin acid, respectively, thereby allowing the bacteria to spread through subcutaneous tissue. They are important in causing cellulitis. Clostridium perfringens causes gas gangrene by secreting alpha toxin, a lecithinase which destroys cell membrane and kills cells. 

	Many parasites are capable of causing malabsorption of nutrients and weight loss by virtue of their persistent presence in the alimentary tract. The protozoa Giardia intestinalis attaches with the help of a sucking disc to the surfaces of intestinal epithelial cells, causing a disturbance of intestinal function and malabsorption of fat. Patients often complain of persistent looseness of bowels and mild steatorrhoea. The adult worms of Ascaris lumbricoides live in small intestine and can disturb digestion and nutrition. A heavy worm burden may contribute to malnutrition, especially in children in the developing countries. Taenia saginata attach to the gut wall and sometimes causes epigastric discomfort, flatulence, hunger sensations and weight loss. 

	The prolonged presence of the microbe or structures produced by them in the body are responsible for many diseases caused by parasites. Echinococcus granulosus causes unilocular hyatid cyst disease by formation of large fluid-filled cysts that contains thousands of individual scoleces. The cysts act as space-occupying lesion, putting pressure on adjacent tissue. Cysts in the lungs can erode into a bronchus, causing bloody sputum while cerebral cysts can cause headaches and focal neurologic signs. Later, if the cyst ruptures, life-threatening anaphylaxis can occur with spread of protoscoleces. Cutaneous larva migrans is a cutaneous lesion resulting from exposure of unprotected skin of humans to filariform larvae of canine, feline and human strains of hookworms, and to human and non-human strains of Strongyloides. The filariform of non-human hookworms are usually unable to penetrate below the stratum germinativum of human skin. A tunnel is formed with the corium as a floor and the stratum granulosum as a roof. The disease manifests as a red itchy papule which becomes elevated and vesicular, causing an intense pruritus and possible secondary infection of the infected skin. A more serious form of infection occurs in visceral larva migrans, characterized by the presence of granulomatous lesions due to prolonged migration and persistence of Toxocara larvae in the tissues. 

	In some microbial infections, the body’s immune system is unable to clear the invading microbes completely and there remains a chronic state of inflammation mounted against the microbe. Mycobacteria induces a granulomatous infection in the body, where the bacteria remains intracellularly in macrophages. The T-cell response against the mycobacteria antigens leads to the formation of granulomas consisting of a central area of giant cells containing tubercle bacilli surrounded by a zone of epitheloid cells. These granulomatous lesions are the main pathogenic causes of the disease tuberculosis. Secondary tuberculosis occurs many years after primary infection with cavitation of the lung caused by destruction of lung tissues. In miliary tuberculosis, mycobacteria are widely disseminated via the bloodstream and granulomas grow all over the body. Chronic inflammation of the liver occurs in 3% of all cases of hepatitis B. After entering blood, the virus infects hepatocytes, causing necrosis and inflammation. Immune attack against viral antigens on infected hepatocytes is mediated by cytotoxic T cells which cause permanent liver damage in chronic cases,leading to liver dysfunction and cirrhosis and ultimately hepatocellular carcinoma. The persistent presence of schistosoma eggs in the liver induce granulomas, which lead to fibrosis, hepatomegaly, portal hypertension and splenomegaly. 

	Another major mechanism by which bacteria cause disease is the production of toxins. Exotoxins are produced by several gram-positive and gram-negative bacteria. Tetanus toxin, produced by Clostridium tetani, is a neurotoxin that prevents release of the inhibitory transmitter glycine, causing muscle spasms best exemplified by spasm of the jaw and neck muscles. Botulium toxin, produced by Clostridium botulinum, is a neurotoxin that blocks the release of acetylcholine at the synapse, producing paralysis. Toxic shock syndrome toxin produced by certain strains of Staphylococcus aureus, binds directly to class II major histocompatibility proteins without intracellular processing. This complex interacts with the T cell receptor of many helper T cells causing the release of large amounts of interleukins, especially interleukin-1 and interleukin-2. They produce many of the signs and symptoms of toxic shock. Endotoxins are lipopolysaccharides which are integral parts of the cell walls of both gram-negative rods and cocci. All endotoxins produce the same generalized effects of fever and shock. 

	There are certain diseases in which cell killing by immunologic attack plays an important role in pathogenesis. Cytotoxic T cells are involved in the pathogenesis of hepatitis caused by hepatitis A, B, and C viruses. Immune-mediated pathogenesis also occurs when virus-antibody-complement complexes form and are deposited in various tissues. Immune complexes play a role in producing the arthritis characteristic of early stages of hepatitis B and disseminated gonococcal infection and acute glomerulonephritis seen occasionally with infection by Streptococcus pyogenes due to deposition of antigen-antibody complexes on glomerular basement membrane. Rheumatic fever occurs some 3-4 weeks after primary infection by Streptococcus pyogenes and is caused by cross-reacting B and T cell responses to streptococcal antigens bound to host components. Immune responses are postulated to play a critical role in the pathogenesis of dengue hemorrhagic syndrome. Non-neutralizing antibodies form complexes with the dengue virus which are then internalized into phagocytes where it replicates and spread. The antigen-antibody complex activates complement, leading to increased vascular permeability, shock and hemorrhage. 

	Lastly, some microbes have been implicated as causes or inducers of certain cancers. Epstein-Barr virus is associated with nasopharyngeal carcinoma, Burkitt’s lymphoma and B cell lymphoma. The human papillomavirus 16 and 18 are implicated in carcinoma of the uterine cervix. Molecular mechanisms appear to be the pathogenic mechanisms employed by these virus in the causation of disease. In malignant cells, viral DNA is integrated into host cell DNA in the vicinity of cellular oncogenes and E6 and E7 are overexpressed. Chronic hepatitis B infection greatly increases the risk of hepatocellular carcinoma. Chronic recurrent cholangitis due to infection by the oriental liver fluke, Clonorchis sinensis, can lead to development of cholangiocarcinoma. 

	Many microbial infections are not well controlled or eradicated due to the inability of the body’s immune system to cope with the pathogenicity of the microbes. Two main mechanisms are involved here: direct killing of the offensive pathogens and neutralizing of its infectivity or toxins. Killing of microbes is effected by macrophages, neutrophils, eosinophils, natural killer cells and cytotoxic T cells. Macrophages and neutrophils ingest bacteria, viruses and other foreign particles. The organism is surrounded by a pseudopodia which then fuse to completely enclose it in an endocytotic vesicle called a phagosome. This then fuses with the cytoplasmic granules which discharge their contents exposing the organism to lysosomal enzymes. Killing is greatly enhanced by the generation of hydrogen peroxide and superoxide by enzymatic reduction of oxygen. They have Fc receptors that interact with the Fc portion of immunoglobulins, thereby enhancing the uptake of opsonized organisms. Eosinophils are phagocytic cells similar to neutrophils but is directed specifically towards parasitic infections. All eosinophils have receptors for IgE which is important in the destruction of parasites. IgE produced by plasma cells in response to parasitic infections induce degranulation of eosinophil granules, releasing many toxic substances such as major basic protein which bind to the body of the parasites, killing it. Viruses are killed specifically in another manner by interferons, glycoproteins produced by leukocytes and fibroblasts. Cytotoxic T cells kill microbe-infected cells by inducing apotosis in them via the Fas ligand or by secretion of granzymes and perforins which punch holes in the target-cell membrane. Antibodies produced by B lymphocytes in response to the primary microbial infection are able to bind to viruses or to bacterial toxins, thereby preventing these substances from affecting host cells. They also enhance the immune response by binding to the microbes, acting as opsonins to facilitate recognition and phagocytosis of microbes and activation of the complement system.