Читать книгу Principles of Virology, Volume 2 - Jane Flint, S. Jane Flint - Страница 73

Humans consist of at least as many bacterial cells as human cells; we are “metaorganisms.” Our gastrointestinal tract teems with bacteria, most of which aid in food digestion and promote health. Consequently, both our eukaryotic defenses and the commensal bacteria that occupy the intestine can be barriers to some viral infections.

In many cases, however, viruses have been selected that take advantage of commensal bacteria to facilitate viral infection of the host. For example, when the intestinal microbiota of mice was depleted with antibiotics before inoculation with poliovirus, an enteric virus, the animals were found to be less susceptible to disease. Further investigation showed that poliovirus binds lipopolysaccharide, the major outer component of Gram-negative bacteria, and exposure of poliovirus to bacteria enhanced host cell association and infection. Furthermore, the presence of bacteria also enhances infections by three other unrelated enteric viruses: reovirus, mouse mammary tumor virus, and murine norovirus. These results indicate that interactions with intestinal microbes can promote some enteric virus infections.

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While passage from the mouth to the stomach is generally considered a quick trip following a swallow, cells in the oropharynx (for example, the tonsils and the back of the throat) appear to be permissive for human papillomaviruses, which can cause oropharyngeal squamous cell carcinoma. Papillomaviruses, traditionally thought to be restricted to the genitourinary tract, are likely delivered to the throat during oral sex and can affect both men and women, as both semen and vaginal secretions can carry infectious papilloma virus particles.

Once in the stomach, a virus particle must endure stomach acid, which typically has a pH of 1.5 to 3.0, sufficiently low to denature most proteins of incoming food and many viruses. Mucus is also abundant in the stomach, where it coats the lining and helps to prevent the highly corrosive gastric acid from attacking the stomach itself. Mucus also serves as a trap for virus particles, much as in the respiratory tract.

Nearly the entire small intestinal surface is covered with columnar villous epithelial cells with apical surfaces that are densely packed with microvilli (Fig. 2.9). This brush border, together with a surface coat of glycoproteins and glycolipids and the overlying mucus layer, is permeable to electrolytes and nutrients but presents a barrier to microorganisms. Once in the small intestine, pathogens can also be targeted by small antimicrobial peptides called defensins, secreted by Paneth cells, which lie at the base of the microvillus crypt. These small (∼30-amino-acid) peptides serve primarily to inactivate invasive or foreign bacteria by destabilizing the bacterial cell wall or by interfering with bacterial metabolism. While a widely held view is that defensins exert their antimicrobial functions by disrupting lipid membranes, studies with viruses, including nonenveloped viruses without a lipid coat, reveal more diverse functions of these peptides, including inhibitory effects on viral entry and movement to the nucleus. In addition, defensins can activate and shape the host immune response, limiting infections indirectly.

Despite formidable barriers, some viruses reproduce extensively in intestinal epithelial cells. Scattered throughout the intestinal mucosa are lymphoid follicles that are covered on the luminal side with a specialized epithelium consisting mainly of columnar absorptive cells and M (membranous epithelial) cells. Some viruses actively reproduce only within M cells and not underlying tissues, remaining localized in the gut. For example, infection by human rotavirus and the coronavirus transmissible gastroenteritis virus destroys M cells, resulting in mucosal inflammation and diarrhea, but spread beyond the gastrointestinal tract does not occur. Conversely, the M cell may be a portal for deeper penetration into the host. The M cell is very thin, resulting in a membranelike bridge that separates the intestinal lumen from the subepithelial space. M cells 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.