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Junctional adhesion molecule-A is required for hematogenous dissemination of reovirus.

ABSTRACT: Diverse families of viruses bind immunoglobulin superfamily (IgSF) proteins located in tight junctions (TJs) and adherens junctions of epithelium and endothelium. However, little is known about the roles of these receptors in the pathogenesis of viral disease. Junctional adhesion molecule-A (JAM-A) is an IgSF protein that localizes to TJs and serves as a receptor for mammalian reovirus. We inoculated wild-type (WT) and isogenic JAM-A(-/-) mice perorally with reovirus and found that JAM-A is dispensable for viral replication in the intestine but required for systemic dissemination. Reovirus replication in the brain and tropism for discrete neural regions are equivalent in WT and JAM-A(-/-) mice following intracranial inoculation, suggesting a function for JAM-A in reovirus spread to extraintestinal sites. JAM-A promotes reovirus infection of endothelial cells, providing a conduit for the virus into the bloodstream. These findings indicate that a broadly expressed IgSF viral receptor specifically mediates hematogenous dissemination in the host.

SUBMITTER: Antar AA

PROVIDER: S-EPMC2642927 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Junctional adhesion molecule-A is required for hematogenous dissemination of reovirus.

Antar Annukka A R AA Konopka Jennifer L JL Campbell Jacquelyn A JA Henry Rachel A RA Perdigoto Ana L AL Carter Bruce D BD Pozzi Ambra A Abel Ty W TW Dermody Terence S TS

Cell host & microbe 20090101 1

Diverse families of viruses bind immunoglobulin superfamily (IgSF) proteins located in tight junctions (TJs) and adherens junctions of epithelium and endothelium. However, little is known about the roles of these receptors in the pathogenesis of viral disease. Junctional adhesion molecule-A (JAM-A) is an IgSF protein that localizes to TJs and serves as a receptor for mammalian reovirus. We inoculated wild-type (WT) and isogenic JAM-A(-/-) mice perorally with reovirus and found that JAM-A is disp ...[more]

PMID: 19154988

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Project description:Nonstructural protein ?1s is a critical determinant of hematogenous dissemination by type 1 reoviruses, which reach the central nervous system (CNS) by a strictly blood-borne route. However, it is not known whether ?1s contributes to neuropathogenesis of type 3 reoviruses, which disseminate by both vascular and neural pathways. Using isogenic type 3 viruses that vary only in ?1s expression, we observed that mice survived at a higher frequency following hind-limb inoculation with ?1s-null virus than when inoculated with wild-type virus. This finding suggests that ?1s is essential for reovirus virulence when inoculated at a site that requires systemic spread to cause disease. Wild-type and ?1s-null viruses produced comparable titers in the spinal cord, suggesting that ?1s is dispensable for invasion of the CNS. Although the two viruses ultimately achieved similar peak titers in the brain, loads of wild-type virus were substantially greater than those of the ?1s-null mutant at early times after inoculation. In contrast, wild-type virus produced substantially higher titers than the ?1s-null virus in peripheral organs to which reovirus spreads via the blood, including the heart, intestine, liver, and spleen. Concordantly, viral titers in the blood were higher following infection with wild-type virus than following infection with the ?1s-null mutant. These results suggest that differences in viral brain titers at early time points postinfection are due to limited virus delivery to the brain by hematogenous pathways. Transection of the sciatic nerve prior to hind-limb inoculation diminished viral spread to the spinal cord. However, wild-type virus retained the capacity to disseminate to the brain following sciatic nerve transection, indicating that wild-type reovirus can spread to the brain by the blood. Together, these results indicate that ?1s is not required for reovirus spread by neural mechanisms. Instead, ?1s mediates hematogenous dissemination within the infected host, which is required for full reovirus neurovirulence.

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Junctional adhesion molecule-A is required for hematogenous dissemination of reovirus.

Publications

Junctional adhesion molecule-A is required for hematogenous dissemination of reovirus.

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