Читать книгу Principles of Virology, Volume 2 - Jane Flint, S. Jane Flint - Страница 80

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.