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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.