Pathogenesis and Immunity

The reader is referred back to Chapter 7 where we discussed factors that determine the virulence of influenza viruses. Best understood are the mutations that alter host and/or tissue tropism by changing the affinity of the HA ligand for receptors in which sialic acid is linked to galactose in different configurations, and second the mutations that affect uncoating of the endo-cytosed virion by changing the cleavability of HA and thus its capacity to mediate fusion. However, it is clear that most of the viral genes, especially NP, P, and NA, as well as HA, influence virulence in one way or another.

In Chapter 9 we discussed the pathology of influenza, mentioning some host factors affecting the outcome. In brief, the virus replicates principally in ciliated columnar epithelium of the respiratory tract, producing tracheobronchitis; features include enhanced airway reactivity (bronchospasm) and impaired mucociliary clearance. Primary viral pneumonia is uncommon, but secondary bacterial pneumonia is an important cause of death in the elderly, the very young, the chronically ill, or the immunocompromised.

Factors contributing to innate resistance include the following: (1) the mucus blanket that protects the underlying epithelium, and the continuous beating of cilia that clears invaders from a healthy respiratory tract, (2) soluble mannose-binding lectins, lung surfactants, and sialyl glycoproteins present in mucus and transudates (see Chapter 7), and (3) alveolar macrophages. These and/or other natural defense mechanisms may be suboptimal in the aged, the premature, the pregnant, the pulmonary invalid, the immunocompromised, or the smoker. In Third World countries vulnerability to influenzajsJncrejsed_ by inhaled pollutants (tobacco or wood smoke), malnutrition, prior or coincident infection, or immunosuppression (see Chapter 7).

If the individual has been infected within the past few years by a closely related strain of the same influenza HA subtype, anti-HA antibodies may intercept and neutralize the infecting virions. Argument continues on the relative importance of IgA and IgG antibodies and on their mechanisms of neutralization of influenza virus. Secretory IgA is generally believed to be the most relevant antibody in the upper respiratory tract at least, but serum IgG may provide protection in the lung. At high concentration, polymeric IgA may block attachment of virions to their receptors more effectively than IgG. At low concentration, anti-HA antibodies of both classes have been shown to inhibit uncoating; IgA has been demonstrated to do this by inhibiting both the fusion of HA to endosomal membrane and the separation of Ml from the ribonucleoprotein complex, thus preventing the latter from entering the nucleus.

If preexisting antibody proves inadequate to block the establishment of infection, recovery is dependent on two nonspecific cell types, activated macrophages and natural killer cells, plus two important cytokines, interferon 7 and interleukin-2, and immunologically specific T lymphocytes of two subclasses, CD4+ and CD84. Class I restricted CD8* cytotoxic T cells, recogniz ing determinants on any of the virus-coded proteins, are the most effective in clearing virus from the lower respiratory tract. Most of these Tc cells are elicited by conserved determinants on the internal proteins NP, Ml, and P, or the nonstructural protein NS1, ensuring a useful degree of cross-protection when long-lived memory T cells are activated by a different strain of influenza virus {of the same species, A or B) some years later. Class II restricted CD4+ T cells, particularly if they have cytotoxic potential, can clear low-level infection or less virulent strains, but they are more important as Th cells, and as Td cells secreting cytokines that attract and activate macrophages, NK cells, and T cells. Paradoxically, however, the inflammatory response produced by CD4+ T cells also contributes to the lung consolidation (pneumonia) which may kill the patient.

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