Principles of Virology, Volume 2. S. Jane Flint

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.

BOX 2.8

      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 disseminated, and the infected animals suffer higher morbidity and mortality.

      When spread occurs by neural pathways, innervation at the primary site of inoculation determines which neuronal circuits will be infected. The only areas in the brain or spinal cord that are targets for herpes simplex virus infection are those that contain neurons with axon terminals or dendrites connected to common sites of inoculation in the body. Reactivated herpes simplex virus uses the same neural circuits to return to those sites, where it causes lesions (for example, cold sores in the mouth).

Figure 2.12 Polarized release of viruses from cultured epithelial cells visualized by electron microscopy. (A) Influenza virus released by budding from the apical surface of canine kidney cells. (B) Budding of measles virus on the apical surface of human colon carcinoma cells. (C) Release of vesicular stomatitis virus at the basal surface of canine kidney cells. Arrows indicate virus particles. Magnification, ×324,000. Reprinted from Blau DM, Compans RW. 1996. Semin Virol 7:245–253, with permission. Courtesy of D. M. Blau and R. W. Compans, Emory University School of Medicine, Atlanta, GA.

The blood and neurons are the primary conduits for viruses to gain access to tissues distal to the site of the inoculation, and are discussed in greater detail below.

Hematogenous Spread

Disseminated infections typically occur by transport through the bloodstream (hematogenous spread). Entry may occur through broken blood vessels (human immunodeficiency virus type 1), through direct inoculation (for example, from the proboscis of an infected arthropod vector, a dirty needle, or the bite of a dog, as in West Nile virus, hepatitis C virus, and rabies virus, respectively), or by basolateral release of virus particles from infected capillary endothelial cells. Because every mammalian tissue is nourished by a web of blood vessels, virus particles in the blood have access to all host organs (Fig. 2.13).

Hematogenous spread begins when newly synthesized particles produced at the entry site are released into extracellular fluids and are taken up by the local lymphatic vascular system (Fig. 2.14). Lymphatic capillaries are considerably more permeable than those of the circulatory system, facilitating virus entry. Moreover, as lymphatic vessels ultimately drain into the circulatory system, virus particles in lymph have eventual, free access to the bloodstream. Because the lymphatic system and circulatory system “meet” in lymph nodes, and because nodes are home to lymphocytes and monocytes, some viruses, such as human immunodeficiency virus type 1, replicate extensively in these cells.