Viral Damage to Tissues and Organs

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The mechanisms by which viruses damage cells were discussed at the cellular and subcellular levels in Chapter 5. Here we apply these concepts at the level of tissues and organs. The severity of disease In humans is not necessarily correlated with the degree of cytopathology produced by the virus in vitro. Many viruses that are cytocidal in cultured cells generally do not produce clinical disease; for example, enteroviruses, which cause severe cytopathic effects (CPE) in cultured human cells, usually cause mapparent infections. Conversely, some viruses, such as rabies virus, are noncytocidal in vitro but cause a lethal disease. In some organs a great deal of cell and tissue damage can occur without producing disease; for example, a substantial number of liver cells can be destroyed without significant clinical signs. When damage to cells does impair the function of an organ or tissue, this may be of minor importance in muscle or subcutaneous tissue, but of great importance in key organs such as the heart or the brain. Likewise, tissue edema may be unimportant in most sites in the body but may have serious consequences m Ihe brain, because of the resulting increase in intracranial pressure, or in the lung, where it may interfere with gaseous exchange, or in the heart, where it may interfere with conduction.

Direct Damage by Cytocidal Viruses

Sometimes the whole pathologic picture may be explained by the direct damage to cells caused by a highly cytocidal virus. Mice infected intravenously with a large dose of Rift Valley fever virus, for example, developed overwhelming hepatic necrosis within 4 hours of injection and died by 6 hours, because the virions passed quickly through the Kupffer cells to infect the hepatic cells, which were rapidly lysed. In this experimental model, the defense mechanisms of the host were quite unable to cope with the rapid lethal damage to a vital organ. Similarly, the distribution of paralysis in a patient with poliomyelitis is a direct consequence of the distribution of those particular motor neurons in the anterior horn of the spinal cord that are destroyed by this highly cytocidal virus, leaving the muscles supplied by those motor neurons nonfunctional.

Damage to the Epithelium of the Respiratory Tract

Respiratory viruses initially invade and destroy just a few epithelial cells, but they initiate a lesion which can progressively damage the protective layer of mucus and lay bare more and more epithelial cells. As viral replication progresses, large numbers of progeny virions are budded into the lumen of the airway. Early in infection, the beating of cilia, the primary function of which is to cleanse the respiratory tract of inhaled particles, may actually help to move released progeny virus along the airway, thereby spreading the infection. As secretions become more profuse and viscous, the cilial beating becomes less effective and ceases as epithelial cells are destroyed.

In studies of influenza virus infection in experimental animals, the spread of the infection via contiguous expansion from initial foci often does not stop until virtually every columnar epithelial cell at that airway level is infected. The result is complete denuding of large areas of epithelial surface (Fig. 9-1) and the accumulation in the airways of large amounts of transudates, exudates containing inflammatory cells and necrotic epithelial cell debris. Where infection of the epithelium of the nasal passages, trachea, and bronchi proceeds to a fatal outcome, there are usually one or more of three complications: bacterial superinfection (nurtured by the accumulation of fluid and necrotic debris in the airways), infection and destruction of the lung parenchyma and the alveolar epithelium, and/or blockage of airways that are so small in diameter that mucous plugs cannot be opened by forced air movements. Blockage of the airways is of most significance in the newborn. In all of these complications there is hypoxia and a pathophysiologic cascade that leads to acidosis and uncontrollable fluid exudation into airways.

Fig. 9-1 Scanning electron micrographs showing the adherence of Pwudomonas aeruginosa to the mouse trachea (bar, 2 |j.m) (A) Norma! mouse trachea, showing a single bacterium (arrow) on a serous cell- (B) Microcolony adhering to desquamating cells in an influenza virus-infected trachea- [From R Ramphal, P M. Small, J. W Shands, Jr , W. Fischlschweiger, and P. A. Small, Jr hifccf IwiuHH. 27, 6H (1980) Courtesy Dr P. A Small, Jr]

Fig. 9-1 Scanning electron micrographs showing the adherence of Pwudomonas aeruginosa to the mouse trachea (bar, 2 |j.m) (A) Norma! mouse trachea, showing a single bacterium (arrow) on a serous cell- (B) Microcolony adhering to desquamating cells in an influenza virus-infected trachea- [From R Ramphal, P M. Small, J. W Shands, Jr , W. Fischlschweiger, and P. A. Small, Jr hifccf IwiuHH. 27, 6H (1980) Courtesy Dr P. A Small, Jr]

Degeneration of respiratory tract epithelial surfaces during influenza infection is extremely rapid, but so is regeneration. In studies of influenza in ferrets, for example, it has been shown that the development of a complete new columnar epithelial surface via hyperplasia of remaining transitional cells may be complete in a few days. The transitional epithelium and the newly differentiated columnar epithelium that arises from it are resistant to infection, probably by virtue of interferon production and a lack of virus receptors. The role of other host defenses, including soluble factors such as mannose-binding lectins and lung surfactants, as well as macrophages, NK cells, IgA and IgG antibody, and T-eel I-media ted immune mechanisms in terminating the infection was discussed in Chapters 7 and 8.

Damage lo the Epithelium of the Intestinal Tract

The principal agents causing viral diarrhea in children are the rotaviruses; other viruses that produce diarrhea in children and adults include the cal-iciviruses, astroviruses, certain adenoviruses, and perhaps coronaviruses. Infection occurs by ingestion, and the incubation period is very short. Rotaviruses infect cells at the tip of the villus and cause marked shortening and occasional fusion of adjacent villi (Fig. 9-2), so that the absorptive surface of the intestine is reduced, resulting in fluid accumulation in the lumen of the gut and diarrhea. Infection generally begins in the proximal part of the small intestine and spreads progressively to the jejunum and ileum and sometimes to the colon. The extent of such spread depends on the initial dose, the virulence of the virus, and the immunologic status of the host. As the infection progresses, the absorptive cells are replaced by immature cuboidal epithelial cells whose absorptive capacity and enzymatic activity are greatly reduced. These cells are relatively resistant to viral infection, so that the disease is often self-limiting if dehydration is not so severe as to be lethal. The rate of recovery is rapid, since the crypt cells are not damaged.

Fluid loss in viral infections of the inlesttnal tract is mainly a loss of extracellular fluid due to impaired absorption, and osmotic loss due primarily to the presence of undigested lactose in the lumen (in infants), rather than active secretion As virus destroys the absorptive cells there is a loss of those enzymes responsible for the digestion of disaccharides, and the loss of differentiated cells diminishes glucose carrier, sodium carrier, and Na t",K1 -ATPase activities. This leads to a Joss of sodium, potassium, chloride, bicarbonate, and water, and the development of acidosis. Another cause of acidosis is the increased microbial activity associated with the fermentation of undigested milk. Acidosis can create a K+ ion exchange across the cellular membrane, affecting cellular functions that maintain the normal potassium concentration.

Diarrhea Rotavirus

Fig, 9-2 Scanning electron and light micrographs of intestinal (issues from a gnotohiotic calf sacrificed 30 minutes after onset of rotavirus diarrhea (A) Proximal small intestine with shortened villi and a denuded villus tip (second from right) {hematoxylin and eosin stain, magnification x 120) (B) Appearance of the same levelof intestine as in (A) by stanning electron microscopy, depicting denuded villi (magnification x 180) (C) Distal small intestine with normal vacuolated epithelial cells and normal villi (hematoxylin and eosm stain, magnilication x 75) (D) Same area as in (C) seen by scanning electron microscopy Epithelial cells appear round and protruding (magnification- x 210) [from C A. Melius, R G Wyatt, and A. Z. Kapikian, Vef Pathol 14, 273 (1977); and A Z Kapikian and R G Wyatt, m "Textbook of Pediatric Infectious Diseases" (R. D Feigin and J D Cherry, eds ), 3rd Ed., p. 661 Saunders, Philadelphia, Pennsylvania, 1992 Courtesy Dr A Z Kapikian j

Hypoglycemia owing to decreased intestinal absorption, inhibited gly-coneogenesis, and increased glycolysis follow, completing a complex of pathophysiologic changes that, if not promptly corrected by restoration of fluids and electrolytes, results in death.

Epithelial Damage Predisposes to Secondary Bacterial Infection

As well as having direct adverse effects, viral infections olten predispose epithelia to secondary bacterial infections, increasing the susceptibility of the respiratory tract, for example, to bacteria that are normal commensals in the nose and throat (see Fig. 9-1). Thus, infections with influenza virus may destroy ciliated epithelia and cause exudation, allowing pneumococci and other bacteria to invade the lungs and cause secondary bacterial pneumonia, which is often the cause of death in elderly people suffering from influenza. Conversely, proteases secreted by bacteria may activate influenza virus infec-tivity by proteolytic cleavage of the hemagglutinin. Rhinoviruses and respiratory syncytial virus damage the mucosa of the nasopharynx and sinuses, predisposing to bacterial superinfection which commonly leads to purulent rhinitis, pharyngitis, sinusitis, and sometimes otitis media. Similarly, in the intestinal tract, rotavirus infections may lead to an increase in susceptibility to enteropathogenic Escherichia coli, and the synergistic effect leads to more severe diarrhea.

Physiologic Changes without Cell Death

In some situations infected cells may show no obvious damage, but, as discussed in Chapter 5, specialized cells may carry out their functions less effectively after infection. For example, lymphocytic choriomeningitis virus infection of hybridoma cells appears harmless, but less antibody is produced by infected than by uninfected cells. In mice, the same virus has no cytopathic effect on cells of the anterior pituitary, but the output of growth hormone is reduced and as a result the mice are runted; likewise, persistent infection of insulin-producing islet cells in the pancreas may result in a lifelong elevation of blood glucose levels (diabetes). Other viruses may indirectly alter the expression of cell surface MHC molecules, leading to destruction of the infected cells by immunologic mechanisms; thus, enhanced class II MHC expression after infection of glial cells by mouse hepatitis virus, perhaps due to the production of interferon -y, may render these cells susceptible to immune cytolysis by Tc cells.

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