Direct spread of reovirus from the intestinal lumen to the central nervous system through vagal autonomic nerve fibers.

Morrison, Lynda A.; Sidman, Richard L.; Fields, Bernard N.

doi:10.1073/pnas.88.9.3852

Cited by 101 publications

(76 citation statements)

References 30 publications

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“…From the bloodstream, virus gains access to sites of secondary replication (46). To determine whether reovirus disseminates from the respiratory tract by the hematogenous route, we quantified virus in the blood on days 1, 2, 3, and 5 after intranasal inoculation with 10 7 PFU of T1L, T3D C , or T3D F .…”

Section: Resultsmentioning

confidence: 99%

Genetic Determinants of Reovirus Pathogenesis in a Murine Model of Respiratory Infection

Nygaard

Lahti

Ikizler

et al. 2013

J Virol

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Many viruses invade mucosal surfaces to establish infection in the host. Some viruses are restricted to mucosal surfaces, whereas others disseminate to sites of secondary replication. Studies of strain-specific differences in reovirus mucosal infection and systemic dissemination have enhanced an understanding of viral determinants and molecular mechanisms that regulate viral pathogenesis. After peroral inoculation, reovirus strain type 1 Lang replicates to high titers in the intestine and spreads systemically, whereas strain type 3 Dearing (T3D) does not. These differences segregate with the viral S1 gene segment, which encodes attachment protein 1 and nonstructural protein 1s. In this study, we define genetic determinants that regulate reovirus-induced pathology following intranasal inoculation and respiratory infection. We report that two laboratory isolates of T3D, T3D C and T3D F , differ in the capacity to replicate in the respiratory tract and spread systemically; the T3D C isolate replicates to higher titers in the lungs and disseminates, while T3D F does not. Two nucleotide polymorphisms in the S1 gene influence these differences, and both S1 gene products are involved. T3D C amino acid polymorphisms in the tail and head domains of 1 protein influence the sensitivity of virions to protease-mediated loss of infectivity. The T3D C polymorphism at nucleotide 77, which leads to coding changes in both S1 gene products, promotes systemic dissemination from the respiratory tract. A 1s-null virus produces lower titers in the lung after intranasal inoculation and disseminates less efficiently to sites of secondary replication. These findings provide new insights into mechanisms underlying reovirus replication in the respiratory tract and systemic spread from the lung. Many viruses enter host organisms by invading mucosal surfaces, including those that line the respiratory tract. Infection by some pneumotropic viruses is restricted to the respiratory tract, whereas others replicate in the lung and disseminate to sites of secondary replication. Mammalian orthoreoviruses (reoviruses) naturally infect both the respiratory and gastrointestinal tracts (1). Reovirus strains differ in the capacity to replicate at mucosal sites and disseminate systemically. Studies of strain-specific differences in reovirus mucosal infection and systemic spread have enhanced an understanding of viral determinants and molecular mechanisms that regulate reovirus pathogenesis. For example, after peroral or intratracheal inoculation, reovirus strain type 1 Lang (T1L) replicates to higher titers than does strain type 3 Dearing (T3D) (2). This difference in replication efficiency at the site of primary replication segregates with the reovirus S1 gene segment (2, 3). Like T1L, reassortant virus 3HA1, with nine gene segments from T3D and an S1 gene from T1L, replicates to high titers in mucosal tissues (2). In contrast, reassortant virus 1HA3, with nine gene segments from T1L and an S1 gene from T3D, fails to replicate to high titers at those sit...

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Section: Resultsmentioning

confidence: 99%

Genetic Determinants of Reovirus Pathogenesis in a Murine Model of Respiratory Infection

Nygaard

Lahti

Ikizler

et al. 2013

J Virol

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“…Paralytic poliomyelitis occurs as a result of neuronal destruction. In the reovirus serotype 3 infection in the newborn mouse model, reovirus first replicates in the lymphoid tissues of the gastrointestinal tract, then rapidly spreads to the mesenteric lymph nodes and produces viraemia (Mann et al, 2002;Morrison et al, 1991). Within 2 days of inoculation, viral titre increases in skeletal muscle and other extraneural sites and shortly thereafter is detected in the CNS.…”

Section: Discussionmentioning

confidence: 99%

A murine oral enterovirus 71 infection model with central nervous system involvement

Chen

Wang

et al. 2004

Journal of General Virology

140

136

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Enterovirus 71 (EV71) infection causes a myriad of diseases from mild hand-foot-and-mouth disease or herpangina to fatal meningoencephalitis complicated with neurogenic pulmonary oedema. Its pathogenesis, especially the CNS involvement, is not clearly understood. The aim of this study was to set up a mouse EV71 infection model with CNS involvement. EV71 virus was administrated orally to neonatal mice. The EV71-infected mice manifested a skin rash at an early stage and hind limb paralysis or death at a later stage. Immunohistochemical staining and virus isolation demonstrated that EV71 replicated in the small intestine, induced viraemia and spread to various organs. Kinetic studies showed that EV71 antigen was first detected in the intestine at 6 h, in the thoracic spinal cord at 24 h, in the cervical spinal cord at 50 h and in the brain stem at 78 h post-infection. Leukocyte infiltration was evident in the spinal cord and brain stem. Furthermore, EV71 virus could be transmitted to littermates within the same cage.

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“…One mechanism for enhanced spread might involve sialic acid-mediated tropism of T3SA+ for a circulating cell type. It is known that sialic acid-binding T3 strains replicate within submucosal lymphoid populations in the intestine (4,53,54), and it is possible that T3SA+ preferentially infects circulating monocytes, lymphocytes, or dendritic cells. The observation that titers of T3SA+ increase early (day 4 after inoculation) in the spleen, a highly vascular organ, suggests that this strain may be more efficient at entering the host blood stream following intestinal replication.…”

Section: Discussionmentioning

confidence: 99%

“…Since almost all detailed studies of T3 reovirus pathogenesis have used sialic acid-binding strains (4,5,25,26,28), little is known about the role of sialic acid in determining reovirus tropism and disease in the infected host. Some cultured cell lines, including murine erythroleukemia cells (MEL cells), support binding and infection of only those reovirus strains that bind sialic acid (36,37).…”

mentioning

confidence: 99%

Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease

Barton¹,

Youree²,

Ebert³

et al. 2003

J. Clin. Invest.

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Infection of neonatal mice with some reovirus strains produces a disease similar to infantile biliary atresia, but previous attempts to correlate reovirus infection with this disease have yielded conflicting results. We used isogenic reovirus strains T3SA– and T3SA+, which differ solely in the capacity to bind sialic acid as a coreceptor, to define the role of sialic acid in reovirus encephalitis and biliary tract infection in mice. Growth in the intestine was equivalent for both strains following peroral inoculation. However, T3SA+ spread more rapidly from the intestine to distant sites and replicated to higher titers in spleen, liver, and brain. Strikingly, mice infected with T3SA+ but not T3SA– developed steatorrhea and bilirubinemia. Liver tissue from mice infected with T3SA+ demonstrated intense inflammation focused at intrahepatic bile ducts, pathology analogous to that found in biliary atresia in humans, and high levels of T3SA+ antigen in bile duct epithelial cells. T3SA+ bound 100-fold more efficiently than T3SA– to human cholangiocarcinoma cells. These observations suggest that the carbohydrate-binding specificity of a virus can dramatically alter disease in the host and highlight the need for epidemiologic studies focusing on infection by sialic acid–binding reovirus strains as a possible contributor to the pathogenesis of neonatal biliary atresia

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Direct spread of reovirus from the intestinal lumen to the central nervous system through vagal autonomic nerve fibers.

Cited by 101 publications

References 30 publications

Genetic Determinants of Reovirus Pathogenesis in a Murine Model of Respiratory Infection

Genetic Determinants of Reovirus Pathogenesis in a Murine Model of Respiratory Infection

A murine oral enterovirus 71 infection model with central nervous system involvement

Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease

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