Principles of Virology, Volume 2. S. Jane Flint

deliver antigens to the underlying lymphoid tissue (termed Peyer’s patches) by transcytosis. In this process, material taken up on the luminal side of the M cell traverses the cytoplasm virtually intact and is delivered to the underlying basal membranes and extracellular space (Fig. 2.9). It is thought that M cell transcytosis is the mechanism by which some enteric viruses, such as poliovirus, gain access to deeper tissues of the host. After crossing the mucosal epithelium, a virus particle could enter lymphatic vessels and capillaries of the circulatory system, facilitating spread within the host. A particularly well studied example is transcytosis of reovirus. After attaching to the M cell surface, reovirus sub viral particles are transported to cells underlying the lymphoid follicle, where the virus is reproduced and then spreads to other tissues.

Figure 2.9 Cellular organization of the small intestine. A simplified view of the cellular composition of the small intestine is shown, with Paneth cells lining the base of the intestinal crypts and M cells providing the thin barrier between the intestinal lumen and the Peyer’s patches beneath. A schematic drawing of the intestinal wall is shown. The small intestine is made up of epithelial, connective, and muscle tissues. Each is formed by different cell types that are organized by cell-cell adhesion within an extracellular matrix. A section of the epithelium has been enlarged, and a typical M cell is shown surrounded by two enterocytes. Lymphocytes and macrophages move in and out of invaginations on the basolateral side of the M cell. Adapted from Siebers A, Finlay BB. 1996. Trends Microbiol 4:22–28.

In some cases, the hostile environment of the alimentary tract actually facilitates infection. For example, reovirus particles are converted by host proteases in the intestinal lumen into subviral particles that are subsequently able to infect intestinal cells.

      While most viruses that can infect via the alimentary tract gain access via the mouth, it is possible for virus particles to enter the body through the lower gastrointestinal tract without passing through the upper tract. Human immunodeficiency virus type 1 can be introduced efficiently in this way as a result of anal intercourse. Anal sex can cause abrasions, stripping away the protective mucus and damaging the epithelial lining, resulting in broken capillaries. Human immunodeficiency virus type 1 particles may then pass through such damaged epithelia to gain access to the blood for transport to lymph nodes, where infection and reproduction can ensue. Once in the lymphoid follicles, the virus can infect migratory lymphoid cells and spread throughout the body. Even without substantial tissue damage, the rectum and colon are lined with lymph nodes that are home to T lymphocytes, the major cell population infected by this virus.

      The microbiome is a major focus of research interest, and studies have begun to shed light on the susceptibility of different individuals to enteric virus infections, and the contributions of the microbiome in protection and disease. Technically, our microbiome is the constellation of bacteria, fungi, and viruses that are present in and on our bodies. However, because the vast majority of these passengers exist within the gut, often the term “microbiome” is taken to mean those species found in the small and large intestine. These microbes have tremendous potential to impact our physiology, both in health and in disease. They aid in regulating metabolism, protect against pathogens, educate the immune system, and, through these basic functions, affect directly or indirectly much of an organism’s physiology. Moreover, the microbiome is as different among individuals as fingerprints, and profiles of resident species change in composition with age and diet. While most studies have focused on the bacterial species that reside in our alimentary canal, in the average healthy human there are five times more viruses than bacteria. The virome refers to the collection of viruses that inhabit the body, and although viruses are typically considered pathogens, it is becoming increasingly clear that, like bacteria, viruses can establish commensal relationships with their hosts. For example, murine norovirus provides benefits to the gut. Germ-free mice have abnormally thin gut villi, the projections within the small intestine that absorb nutrients. While it has been known for some time that providing these mice with gut bacteria can restore villi morphology and function, it was recently shown that introduction of mouse norovirus can have the same beneficial outcome. This beneficial effect of infection may be due indirectly to the induction of interferons, important soluble components of the host immune response.

Eyes

      The epithelia that cover the exposed part of the sclera (the outer fibrocollagenous coat of the eyeball) and form the inner surfaces of the eyelids (conjunctivae) provide the route of entry for several viruses, including some adenovirus types, enterovirus 70, and herpes simplex virus. Every few seconds, the eyelid closes over the sclera, bathing it in secretions that wash away foreign particles. Like the saliva, tears that are routinely produced to keep the eye hydrated also contain small quantities of antibodies and lysozymes. Of interest, the chemical composition of tears differs, depending on whether they are “basal” tears produced constantly in the healthy eye, “psychic tears” produced in response to emotion or stress, or “reflex tears” produced in response to noxious irritants, such as tear gas or onion vapor. The concentration of antimicrobial molecules increases in reflex tears, but not psychic tears, underscoring the fact that host defenses are finely calibrated to respond to changes in the environment.

      The primary function of tears is to wash away dust particles, viruses, and other microbes that land on the eye or under the eyelid. There is usually little opportunity for viral infection of the eye, unless it is injured by abrasion. Direct inoculation into the eye may occur during ophthalmologic procedures or from environmental contamination, such as improperly sanitized swimming pools and hot tubs. In most cases, viral reproduction is localized and results in inflammation of the conjunctiva, a condition called conjunctivitis or “pink eye.” Systemic spread of the virus from the eye is rare, although it does occur; paralytic illness after enterovirus 70 conjunctivitis is one ex ample. Herpesviruses, in particular herpes simplex virus type 1, can also infect the cornea, mainly at the site of a scratch or other injury, and immunocompromised individuals are at greater risk of retinal infection with cytomegalovirus. Such infections may lead to immune destruction of the cornea or the retina and eventual blindness. Inevitably, herpes simplex virus infection of the cornea is followed by spread of the virus to sensory neurons and then to neuronal cell bodies in sensory ganglia, where a latent infection is established. Injury to the eye that allows for viral entry need not be a major trauma: small dust particles or rubbing one’s eyes too aggressively may be sufficient to damage the protective layer and provide an opportunity for virus particles to access permissive cells.

While one may not normally think of eyelashes and eye brows as key components of host defenses, these well-placed patches of hair help to capture fomites that might invade the eye. An intriguing thought is that, as evolution progressed from apes to humans, dense hair was lost from all except a few parts of the body: on top of the head, in the pubic region, and around the eye. It is tempting to speculate that individuals who retained these patches of hair may have had an evolutionary advantage because they were more resistant to certain infections.

Urogenital Tract

      Some viruses, including hepatitis B virus, human immunodeficiency virus type 1, and some herpesviruses, enter the urogenital tract, most typically as a result of sexual practices. Like the alimentary tract, the urogenital tract is well protected by mucus and low pH. The vagina maintains a pH that is typically between 3.4 and 4.5; when the pH increases toward neutrality (as a result of antibiotic use or natural changes in epithelial thickness during the menstrual cycle, for example), many pathogens, including bacteria and yeast, can flourish. Moreover, the vaginal mucosa is separated from the environment by a squamous epithelium that varies in thickness during the menstrual cycle, and that presents a formidable barrier to pathogens. In cases where this lining is thin, such as the zone between the endo- and ectocervix, viruses such as papilloma virus and human immunodeficiency virus type 1 may be able to infect the epithelium and abundant CD4⁺ T cells beneath.