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.
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) 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).
Spread throughout the Host
Following reproduction at the site of entry, virus particles can remain localized or can spread to other tissues. Spread beyond the initial site of infection depends on multiple parameters, including the initial viral dose, the presence of viral receptors on other cells, and the relative rates of immune induction and release of infectious virus particles. Localized infections in the epithelium are usually limited by the physical constraints of the tissue and are brought under control by the intrinsic and innate immune defenses discussed in Chapter 3. An infection that spreads beyond the primary site (usually near the point of viral entry) is said to be disseminated. If many organs are viral targets, the infection is described as systemic. Spread beyond the primary site requires continued breaching of the host’s physical barriers. For example, virus particles may be able to cross a basement membrane when the integrity of that structure is compromised by inflammation and epithelial cell destruction. Below the basement membrane are subepithelial tissues, where virus particles encounter tissue fluids, the lymphatic system, and phagocytes. These host components make substantial contributions to clearing foreign particles, but may also allow infectious virus particles to be carried beyond the primary site of infection.
DISCUSSION
Gender differences in infection and disease
Male and female humans differ in both their susceptibility to infection and in the severity of illness that some infections can cause. In general, males become infected more often than females, likely because females often mount stronger immune responses than males. However, while these responses can result in faster resolution of the infection, they can also contribute to immunopathology, which is seen more in women than men. Adverse reactions to both vaccines and antiviral drugs are also greater in women than in men, perhaps as a result of gender-based differences in hormone type, as well as differences in the metabolism of drugs and vaccines.
Klein SL. 2012. Sex influences immune responses to viruses, and efficacy of prophylaxis and treatments for viral diseases. BioEssays 34:1050–1059.
One important mechanism for avoiding local host defenses and facilitating spread within the body is the directional release of virus particles from polarized cells at a mucosal surface (Volume I, Chapter 12). Virus particles can be released from the apical surface, from the basolateral surface, or from both (Fig. 2.12). After reproduction, particles released from the apical surface are back where they started, that is, “outside” the host. Such directional release facilitates the dispersal of many newly synthesized enteric viruses in the feces (e.g., poliovirus) or the respiratory tract (e.g., rhinoviruses). In general, virus particles released at apical membranes establish a localized or limited infection and do not penetrate deeply beyond the primary site of infection. In such cases, local lateral spread from cell to cell may occur in the infected epithelium, but the underlying lymphatic and circulatory vessels are rarely infected. In contrast, virus particles released from basolateral surfaces of polarized epithelial cells can access underlying tissues, facilitating systemic spread. The consequences of directional release are striking. Sendai virus, which is normally released from the apical surfaces of polarized epithelial cells, causes only a localized infection of the respiratory tract. In stark contrast, a mutant strain of this virus, which is released from both apical and basal surfaces, is
