Reovirus Binding Determinants in Junctional Adhesion Molecule-A

Guglielmi, Kristen M.; Kirchner, Eva; Holm, Geoffrey H.; Stehle, Thilo; Dermody, Terence S.

doi:10.1074/jbc.m702180200

Cited by 53 publications

(68 citation statements)

References 52 publications

(59 reference statements)

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“…The T3D C change at nucleotide 77 confers a valine-to-alanine change at position 22 in the 1 tail and a glutamine-to-histidine change at position 3 in 1s, whereas nucleotide 1234 confers a threonine-to-alanine change at position 408 in the 1 head. These residues are not associated with any known antibody epitope, receptor-binding site, or protease-sensitive region (7,8,(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62). Interestingly, our F virions were treated with HAT protease for 2 h at the concentrations shown.…”

Section: Discussionmentioning

confidence: 89%

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: Discussionmentioning

confidence: 89%

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

Nygaard

Lahti

Ikizler

et al. 2013

J Virol

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“…Reoviruses use the TJ protein JAM-1 as a cellular receptor (Barton et al 2001). The viral surface protein s1 directly interacts with the amino-terminal domain of JAM-1 and disrupts the homodimers of this junction protein (Forrest et al 2003;Campbell et al 2005;Guglielmi et al 2007). …”

Section: Disruption Of Tight Junctions By Enteropathogensmentioning

confidence: 99%

Concepts and Mechanisms: Crossing Host Barriers

Doran

Banerjee

Disson

et al. 2013

Cold Spring Harbor Perspectives in Medicine

111

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“…One dimerization-defective JAM-A mutant we studied has point mutations at two residues (E61A/K63A) predicted by the crystal structure to be required for dimerization (6163), and both mutations have been shown to disrupt dimerization in vitro (Mandell et al, 2004). Mutation of either residue has been shown to result in JAM-A formation of only monomers as assessed by gel filtration (Guglielmi et al, 2007). A second dimerization-defective construct that we tested consists of JAM-A with a deletion of the distal most immunoglobulinlike loop, which is necessary for dimerization (DL1).…”

Section: Introductionmentioning

confidence: 99%