Читать книгу Principles of Virology, Volume 2 - Jane Flint, S. Jane Flint - Страница 81

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) When NA does not contain a lysine at the carboxyl terminus, plasminogen cannot interact with NA and is not activated to plasmin. Therefore, HA is not cleaved. Data from Goto H, Kawaoka Y. 1998. Proc Natl Acad Sci U S A 95:10224–10228.

A final emerging class of cellular macromolecules that can influence viral tropism are small, non-protein-encoding RNA species, called microRNAs. Although these RNAs do not result in new protein production, they can still dramatically affect host cell physiology. For example, microRNA-122 is conserved among vertebrates (but not present in invertebrates), and its expression is highest in the liver, where it likely contributes to fatty acid metabolism. The liver-tropic virus hepatitis C virus depends on microRNA-122 for reproduction. This microRNA binds directly to two adjacent sites close to the 5′ end of hepatitis C virus RNA, impacting RNA stability and genome replication (Volume 1, Chapter 9).

As we learn more about viruses, hosts, and populations, we are discovering that some surprising variables, including the gender of the host, can influence both the frequency and severity of viral infections (Box 2.8).