Principles of Virology, Volume 2. S. Jane Flint

uptake. Interestingly, some intestinal microbes may actually facilitate viral infection (Box 2.5).

      Saliva in the mouth presents an initial obstacle to virus entry. While saliva is mostly water, it does contain lysozymes and other enzymes that aid in the breakdown of food but can also destabilize viral particles. One type of antibody found in saliva, secretory IgA (Chapter 4), may directly bind and inactivate incoming viral particles. A protein known as salivary agglutinin has been reported to directly interfere with influenza virus and human immunodeficiency virus type 1, possibly accounting for why ingestion is not the traditional route of infection by these viruses.

BOX 2.4

      EXPERIMENTS

       Olfactory neurons: front-line sentinels

      Neurons within the olfactory mucosa are a potential entry point for respiratory viruses that can replicate in neurons, including measles, mumps, rubella, and varicella-zoster virus. Olfactory neurons are unusual in that their cell bodies are present in the olfactory epithelia and their axon termini are in synaptic con tact with olfactory bulb neurons. The olfactory nerve fiber passes through the skull via an opening called the arachnoid, and thus viruses that are present within the nasal mucosa are just one synapse away from the brain. Yet infections of the central nervous system (CNS) rarely occur. Why aren’t CNS infections more common via this route? Studies in mice have revealed some mechanisms that may prevent this potentially catastrophic outcome. Infection of mice with a neurotropic strain of influenza A Olfactory mucosa Mitral cell neurons of olfactory bulb Receptor cell axon terminal Subarachnoid space Dura Cribriform plate Receptor cell axon Receptor cell body Olfactory rods virus resulted in rapid apoptosis (cell suicide) of olfactory bulb neurons, coincident with activation of local phagocytes. Mice survived the challenge, raising the possibility that early activation of apoptotic pathways in olfactory neurons may prevent spread of influenza into the brain. Moreover, infection with both RNA and DNA viruses triggers the induction of long distance interferon signaling. Even in the absence of neurotropic virus infection, interferon stimulated proteins are synthesized in remote, posterior regions of the brain, activating an antiviral state and preventing further virus invasion.

       Mori I, Goshima F, Imai Y, Kohsaka S,Sugiyama T, Yoshida T, Yokochi T, Nishiyama Y, Kimura Y. 2002. Olfactory receptor neurons prevent dissemination of neurovirulent influenza A virus into the brain by undergoing virus-induced apoptosis. J Gen Virol 83: 2109–2116.

       van den Pol AN, Ding S, Robek MD. 2014. Long-distance interferon signaling within the brain blocks virus spread. J Virol 88:3695–3704.

BOX 2.5

      EXPERIMENTS

       Commensal bacteria aid virus infections in the gastrointestinal tract

      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.

       Baldridge MT, Nice TJ, McCune BT, Yokoyama CC, Kambal A, Wheadon M, Diamond MS, Ivanova Y, Artyomov M, Virgin HW. 2015. Commensal microbes and interferon-λ determine persistence of enteric murine norovirus infection. Science 347:266–269.

       Jones MK, Watanabe M, Zhu S, Graves CL, Keyes LR, Grau KR, Gonzalez-Hernandez MB, Iovine NM, Wobus CE, Vinjé J, Tibbetts SA, Wallet SM, Karst SM. 2014. Enteric bacteria promote human and mousenorovirus infection of B cells. Science 346:755–759.

       Kane M, Case LK, Kopaskie K, Kozlova A, MacDear-mid C, Chervonsky AV, Golovkina TV. 2011. Successful transmission of a retrovirus depends on the commensal microbiota. Science 334:245–249.

       Kuss SK, Best GT, Etheredge CA, Pruijssers AJ, Frierson JM, Hooper LV, Dermody TS, Pfeiffer JK. 2011. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science 334:249–252.

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