Biomedical subjects

Rebecca J Duerst

Publications and source records attributed to Rebecca J Duerst.

4 recordsLinked to original sources

PubMed2006

Herpes simplex virus type 2-mediated disease is reduced in mice lacking RNase L.

RNase L helps mediate the antiviral state induced by type I interferons (IFNalphabeta). Although herpes simplex virus (HSV) encodes inhibitors of the IFNalphabeta-induced antiviral response, the IFNalphabeta system serves the body as a first line of defense against HSV. We investigated whether RNase L limits HSV-2 replication and virulence. RNaseL(-/-) and wild-type C57BL/6 mice were infected intravaginally with HSV-2 strain 333. Although initial replication in the genital epithelium was similar, mice lacking RNase L developed less severe genital and neurologic disease than wild-type mice, survived longer, and contained lower viral titers in the nervous system. CD4(+) T cell infiltration into the genital tract and spinal cord of RNase L(-/-) mice was reduced, suggesting that a restricted inflammatory response may account for reduction in disease. Thus, RNase L does not play a significant role in control of HSV-2 infection in vivo; instead, RNase L may regulate aspects of the inflammatory response that contribute to disease.

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PubMed2004

Herpes simplex virus 2 virion host shutoff protein interferes with type I interferon production and responsiveness.

The herpes simplex virus 2 (HSV-2) virion host shutoff (vhs) protein is a ribonuclease contained in the virion tegument. vhs-deficient mutants of HSV-2 are profoundly attenuated in vivo, and we have previously shown that replication and virulence of vhs-deficient HSV-2 are largely restored to levels of wild-type virus in mice lacking the interferon alpha/beta receptor (IFNalphabetaR(-/-)). This result demonstrated that HSV-2 vhs interferes with the type I IFN response, but whether vhs inhibits production of type I IFN or synthesis or function of key mediators of the IFN-induced antiviral state was not clear. Here we address these questions using primary murine embryonic fibroblasts (MEFs), which produce and respond to IFNalphabeta. The vhs-deficient HSV-2 strain 333d41 replicated similarly to wild-type virus (333 clone SB5) and vhs rescue virus (333d41(R)) after infection of MEFs at high moi, but at low moi, 333d41 replication was severely attenuated, recapitulating the attenuated phenotype of vhs-deficient HSV-2 in vivo. Replication of 333d41 at low moi was restored to levels of wild-type virus in MEFs lacking the IFNalphabeta receptor or when IFNalphabeta was neutralized, thus establishing the IFNalphabeta response as the sole mechanism attenuating vhs-deficient HSV-2 replication in MEFs. MEFs infected with 333d41 produced >50-fold more IFNalphabeta than cells infected with 333 and 333d41(R). Pretreatment of MEFs with type I IFN inhibited replication of 333d41 more than 333 and 333d41(R), indicating that vhs also interferes with activation of the IFNalphabeta-induced antiviral response. We therefore examined vhs interference with PKR and RNase L, two key mediators of the IFNalphabeta response. 333d41 replication was restored to wild-type levels after low moi infection of PKR(-/-) and RNase L(-/-) MEFs, and was not inhibited in PKR(-/-) MEFs pretreated with IFNalpha. Together, these observations indicate that HSV-2 vhs is a broad and potent countermeasure to the IFN-mediated antiviral response in IFN-naïve and -sensitized MEFs.

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PubMed2003

Innate immunity to herpes simplex virus type 2.

Herpes simplex virus type 2 (HSV-2) is responsible for most cases of genital herpes and also can cause fatal disseminated disease in perinatally infected newborns. Sexually transmitted infections initiate in the skin or mucosa and quickly spread into peripheral nerves to establish latency. Innate immunity, the first line of defense during both primary and recurrent infection, is essential during this period of acute infection to limit initial viral replication and to facilitate an appropriate adaptive immune response. The innate immune response consists of a complex multilayered system of mechanical and secreted defenses, immediate chemokine and IFN responses, and rapidly recruited cellular defenses. HSV has devised equally elaborate strategies to evade or interfere with innate immunity. This review summarizes our current understanding of the innate immune responses to HSV-2 and the mechanisms by which HSV-2 can overcome these barriers. Newly emerging links between products of innate responses and the development of adaptive immune responses are also discussed.

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PubMed2003

Herpes simplex virus type 2 virion host shutoff protein regulates alpha/beta interferon but not adaptive immune responses during primary infection in vivo.

The herpes simplex virus (HSV) virion host shutoff (vhs) protein, the product of the UL41 (vhs) gene, is an important determinant of HSV virulence. vhs has been implicated in HSV interference with host antiviral immune responses, down-regulating expression of major histocompatibility complex molecules to help HSV evade host adaptive immunity. The severe attenuation of vhs-deficient viruses in vivo could reflect their inability to escape immune detection. To test this hypothesis, BALB/c or congenic SCID mice were infected intravaginally (i.vag.) with the HSV type 2 (HSV-2) vhs null mutant 333d41 or the vhs rescue virus 333d41(R). vhs-deficient virus remained severely attenuated in SCID mice compared with rescue virus, indicating that vhs regulation of adaptive immune responses does not influence HSV pathogenesis during acute infection. Innate antiviral effectors remain intact in SCID mice; prominent among these is alpha/beta interferon (IFN-alpha/beta). The attenuation of HSV-2 vhs mutants could reflect their failure to suppress IFN-alpha/beta-mediated antiviral activity. To test this hypothesis, 129 and congenic IFN-alpha/beta receptor-deficient (IFN-alpha/betaR(-/-)) mice were infected i.vag. with wild-type virus, vhs null mutants 333-vhsB or 333d41, or the vhs rescue virus 333d41(R). Whereas vhs-deficient viruses showed greatly reduced replication in the genital mucosa of 129 mice compared with wild-type or vhs rescue viruses, they were restored to nearly wild-type levels of replication in IFN-alpha/betaR(-/-) mice over the first 2 days postinfection. Only wild-type and vhs rescue viruses caused severe genital disease and hind limb paralysis in 129 mice, but infection of IFN-alpha/betaR(-/-) mice restored the virulence of vhs-deficient viruses. vhs-deficient viruses replicated as vigorously as wild-type and rescue viruses in the nervous systems of IFN-alpha/betaR(-/-) mice. Restoration was specific for the vhs mutation, because thymidine kinase-deficient HSV-2 did not regain virulence or the capacity to replicate in the nervous systems of IFN-alpha/betaR(-/-) mice. Furthermore, the defect in the IFN-alpha/beta response was required for restoration of vhs-deficient virus replication and virulence, but the IFN-alpha/beta-stimulated protein kinase R pathway was not involved. Finally, vhs of HSV-2 has a unique capacity to interfere with the IFN-alpha/beta response in vivo, because an HSV-1 vhs null mutant did not recover replication and virulence after i.vag. inoculation into IFN-alpha/betaR(-/-) mice. These results indicate that vhs plays an important role early in HSV-2 pathogenesis in vivo by interfering with the IFN-alpha/beta-mediated antiviral response.

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