Principles of Virology, Volume 2. S. Jane Flint

cells are supported by a dense basement membrane, which raises an additional barrier to viral passage into the tissue (Fig. 2.18 and 2.20). In the central nervous system, the basement membrane, formed in part by astrocytic extensions (called “endfeet”) that align with the basolateral surface of the capillary endothelium, is the foundation of the blood-brain barrier (Fig. 2.21).

      Not all capillaries in tissues adhere to one of these three types: for example, in several well-defined parts of the brain, the capillary epithelium is loosely joined together, and the basement membrane is sparse, affording an easier passage for some neurotropic viruses . These highly vascularized sites include the choroid plexus, a sheet of tissue that lies within the brain ventricles and that produces more than 70% of the cerebrospinal fluid that bathes the spinal cord and affords protective cushioning. Some viruses (mumps virus and certain togaviruses) pass through the capillary endothelium and enter the stroma of the choroid plexus, where they may then cross the epithelium into the cerebrospinal fluid either by transcytosis or by directed release following production of progeny virus particles. Once in the cerebrospinal fluid, infection can spread to the ependymal cells lining the ventricles and the underlying brain tissue (Fig. 2.21). Other viruses (picornaviruses) may infect directly, or be transported across the capillary endothelium. Some viruses (human immunodeficiency virus type 1 and measles virus) cross the endothelium within infected monocytes or lymphocytes (the Trojan Horse approach, described earlier). Increased local permeability of the capillary endothelium, caused, for example, by certain hormones, may also facilitate virus entry into the brain and spinal cord.

Figure 2.20 How viruses travel from blood to tissues with basement membranes. Schematic of a capillary (similar to Fig. 2.19, right), illustrating different pathways by which viruses may leave the blood and enter underlying tissues. Adapted from Nathanson N (ed). 2007. Viral Pathogenesis and Immunity (Academic Press, London, United Kingdom), with permission.

Skin

      In a number of systemic viral infections, rashes are produced when virus particles leave blood vessels and enter the cells that comprise the skin. Viruses that cause rashes include measles virus, rubella virus (German measles), varicella-zoster virus (chicken pox and shingles), some parvoviruses (fifth disease), poxviruses (smallpox), and Coxsackieviruses (hand, foot, and mouth disease). Skin lesions resulting from these infections are notably distinct, distinguished by size, color, frequency, and elevation (an indication of inflammation). Rashes may appear coincident with or subsequent to an infection, although most all appear toward the end of the acute infection. Destruction of cells by virus reproduction and the host immune system are the primary causes of most skin lesions.

      Rashes are not restricted to the skin. Lesions may also occur in mucosal tissues, such as those in the mouth and throat. Because these surfaces are wet, vesicles break down more rapidly than on the skin. During measles infection, ulcerating vesicles in the mouth, called Koplik spots, appear 2 to 4 days before the characteristic skin lesions. Identifying a viral infection early has obvious containment benefits: by the time that the infection is recognized from the skin rash, viral transmission to other individuals may already have occurred.

Figure 2.21 How viruses gain access to the central nervous system. (Left) A summary of the mechanisms by which viruses can enter the brain is shown. CSF, cerebrospinal fluid. (Right) Schematic of the composition of the blood-brain barrier.

Shedding of Virus Particles

      Viruses that cannot spread from host to host face extinction. Just as there are many ways that viruses can infect host species, there are even more ways for them to get out. The release of virus particles from an infected host is called shedding. While most transmission events are attributable to such release, there are some exceptions. These exceptions include vertical transmission of integrated viral genomes in the host germ line from mother to child, and transmission via blood transfusions or organ transplantation, such as can occur with human immunodeficiency virus type 1 and hepatitis viruses.

      During localized infections in or near one of the body openings, shedding can occur from the primary site of virus reproduction. The papillomaviruses cause genital warts; these viruses reproduce locally in the genital epithelium and are transmitted to hosts via sexual contact. In contrast, virus particles that result in disseminated infections can exit the host from many sites. Effective transmission of virus particles from one host to another depends on the concentration of released particles and the mechanisms by which the virus particles are introduced into the next host. The shedding of small quantities of virions may be insufficient to cause new infections, while the shedding of high concentrations may facilitate transmission via minute quantities of tissue or body fluid. For example, the concentration of hepatitis B virus particles in blood can be so high that a few microliters is sufficient to initiate an infection. Similarly, when you receive a mosquito “bite” (actually a sting), a tiny amount (less than a microliter) of its saliva is injected, which may contain sufficient particles to result in widespread infection. An interesting feature of such infections is that the mosquito saliva also numbs the site, stops the blood from clotting, and induces inflammation, which can help to spread the infection.

Respiratory Secretions

Respiratory transmission depends on the density of virus particles in the secretion, and the duration of a liquid droplet in the air. Aerosols are produced during speaking and normal breathing, while coughing produces even more forceful expulsion. Transmission from the nasal cavity is facilitated by sneezing and is much more effective if infection induces the production of nasal secretions. A sneeze from an influenza virus-infected individual produces up to 20,000 droplets (in contrast to several hundred expelled by coughing), although a recent publication assessing influenza virus transmission found almost no virus in a “sneeze vapor”; virtually all infectious virus was found in the liquids expelled during a cough. As noted when we discussed viral entry, the size of a droplet affects its “hang time”: large droplets fall to the ground, but smaller droplets (1 to 4 μm in diameter) may remain suspended in the air for many hours. Such particles may not only come in contact with a naïve host but also penetrate into the lower respiratory tract. Nasal and oral secretions also frequently contaminate hands or tissues. The infection may be transmitted when these objects contact another person’s fingers, and that person in turn touches his or her nose or conjunctiva. In today’s crowded society, the physical proximity of people may select for viruses that spread efficiently by this route. Sneezing and coughing may be the body’s way of trying to eliminate an irritant in the respiratory tract. While it is appealing to speculate that viruses may have been selected that induce thunderous noises and ejection of alarming volumes of body fluids to ensure transmission to new hosts, this hypothesis has not yet been proven (Box 2.12).

Saliva

      Some viruses that reproduce in the lungs, nasal mucosa, or salivary glands are shed into the oral cavity. Transmission may occur through aerosols, as discussed above, via contaminated fingers, or by kissing or spitting. Animals that lick, nibble, and groom may also transmit infections in saliva. Perhaps the best-known human virus that is transmitted in this way is Epstein-Barr virus, which results in mononucleosis,