Principles of Virology, Volume 2. S. Jane Flint

Is intuition a host defense?

      As sentient humans (and animals), we are constantly surveying our environment for dangers and opportunities. Such senses help all organisms to evade predation and to locate food sources but may also be useful in avoiding infections. For example, a rather typical human behavior upon locating some food toward the back of the refrigerator is to sniff it to see if it is still “good,” and people are usually quite adept at knowing when food is no longer acceptable to eat based on smell and appearance. In principle, food surveillance is a kind of quality control to ensure that the items we eat do not carry dangerous microbes. Similarly, avoiding a murky hot tub or declining the advances of a dubious sexual partner could also be considered finely honed skills that may help to avoid contact with pathogens.

The cells in which a virus reproduces obviously influence the kind of disease that can occur, and thus tropism is a crucial parameter of pathogenesis. Human herpes simplex virus is considered neurotropic because of its ability to infect, and be reactivated from, the nervous system, but in fact, this virus can reproduce in many cells and tissues in the host. In most hosts, a localized infection occurs at the site of infection, followed by latent infection of neurons that innervate that tissue. In some individuals with weakened immune systems, such as neonates and the elderly, the virus may cause viremia, enabling access to distal organs, or may cross from the peripheral nervous system to the central nervous system. While rare, both of these outcomes pose serious risk for long-term disease.

Accessibility of Viral Receptors

      A cell may be susceptible to infection if the viral receptor(s) is present and functional. However, the receptor may not be accessible. For example, if the cellular receptor is present only on the basal cell membrane of polarized epithelial cells, a virus that is only exposed to the apical cell surface cannot infect unless it reaches the basolateral surface by some means. Alternatively, if the viral receptor is located between adjacent cells (at the tight junctions), another cell surface protein may be necessary to ferry the virus particle from the exposed cell membrane to the site of the viral receptor (Volume I, Chapter 5). Nonsusceptible (non-receptor-producing) cells can still be infected by alternative routes; for example, virus particles bound to antibodies can be taken up by Fc receptors (see “Immunopathological lesions caused by B cells” in Chapter 4).

Other Host-Virus Interactions That Regulate the Infectious Cycle

      Sequences in viral genomes that control transcription of viral genes, such as enhancers, may be determinants of viral tropism. In the brain, JC polyomavirus reproduces only in oligodendrocytes, because the JC virus enhancer is active only in this cell type. Other examples include the liver-specific enhancers of hepatitis B virus and the keratinocyte-specific enhancer of human papillomavirus type 11.

Cellular proteases, present in some cells but not others, are often required to cleave viral proteins to form the mature infectious virus particle (Volume I, Chapter 13). For example, a cellular protease in the lung cleaves the influenza virus HA0 precursor into two subunits so that fusion of the viral envelope and cell membrane can proceed. In mammals, the reproduction of influenza virus is restricted to epithelial cells of the upper and lower respiratory tracts, and its tropism is thought to be influenced by the production of the protease that processes HA0. This serine protease, called tryptase, is secreted by nonciliated club cells of the bronchial and bronchiolar epithelia (Fig. 2.11), one of the only cell types to do so. Purified tryptase can cleave and activate HA0 in virus particles in vitro. Alteration of the hemagglutinin (HA) cleavage site so that it can be recognized by other cellular proteases dramatically changes the tropism of the virus and its pathogenicity; some highly virulent avian influenza virus strains contain an insertion of multiple basic amino acids at the cleavage site of HA0. This new sequence permits processing by ubiquitous intracellular proteases, such as furins. As a result, these variant viruses are released in active form and are able to infect many organs of birds, including the spleen, liver, lungs, kidneys, and brain. Naturally occurring mutants of this type cause high mortality in poultry farms. These viruses can also infect humans: avian influenza viruses isolated from 16 people in Hong Kong in 1997 contained similar amino acid substitutions at the HA0 cleavage site, and many of these individuals had gastrointestinal, hepatic, and renal symptoms as well as respiratory disease. A virus with such an HA0 site alteration had not been previously identified in humans, and its isolation led to fears that an influenza pandemic was imminent, resulting in the preventative slaughter of all chickens in Hong Kong. Beyond these direct alterations in the viral HA0, changes in other viral proteins can influence HA cleavage indirectly (Box 2.7).

Figure 2.11 Cleavage of influenza virus HA0 by club cell tryptase. Influenza viruses reproduce in respiratory epithelial cells in humans. These virus particles contain the uncleaved form of HA (HA0) and are noninfectious. Club cells secrete a protease, tryptase, which cleaves the HA0 of extracellular particles, thereby rendering the viral particles infectious. Adapted from Tashiro M, Rott R. 1996. Semin Virol 7:237–243, with permission. Note: In previous editions of this text, club cells were referred to as “Clara cells,” named after the German scientist who discovered them. Because Clara was an active member of the Nazi party, in 2013, the lung physiology community elected to change the name of these cells to “club cells.” We have adopted this convention.

BOX 2.7

      DISCUSSION

       A mechanism for expanding the tropism of influenza virus is revealed by analyzing infections that occurred in 1940

      Entry of influenza virus is controlled by two glycoproteins, hemagglutinin (HA) and neuraminidase (NA), present on the viral surface. Initiation of virus infection involves binding to sialic acids on carbohydrate side chains of cellular glycoproteins and glycolipids. Until the isolation of the H5N1 virus from 16 individuals in Hong Kong, viruses with the HA0 cleavage site mutation that permits cleavage by ubiquitous furin proteases had not been found in humans. Similarly, the WSN/33 strain of influenza virus, produced in 1940 by passage of a human isolate in mouse brain, is pantropic in mice. Unlike most human influenza virus strains, WSN/33 can reproduce in cells in culture in the absence of added trypsin, because its HA0 can be cleaved by serum plasmin. Surprisingly, it was found that the NA of WSN/33 is necessary for HA0 cleavage by serum plasmin. This altered NA protein can bind plasminogen, sequestering it on the cell surface, where it is converted to the active form, plasmin (see figure, panel A). Plasmin then cleaves HA0 into HA1 and HA2. Therefore, a change in NA, not in HA, allowed cleavage of HA by a ubiquitous cellular protease. This property may, in part, explain the pantropic nature of WSN/33.

       Goto H, Kawaoka Y. 1998. A novel mechanism for the acquisition of virulence by a human influenza A virus. Proc Natl Acad Sci U S A 95:10224–10228.

       Taubenberger JK. 1998. Influenza virus hemagglutinin cleavage into HA1, HA2: no laughing matter. Proc Natl Acad Sci U S A 95:9713–9715.

      Proposed mechanism for activation of plasminogen and cleavage of HA. (A) Plasminogen binds to NA, which has a lysine at the carboxyl terminus. A cellular protein converts plasminogen to the active form, plasmin. Plasmin then cleaves HA0 into HA1 and HA2. (B)