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Pathogenesis of a model gammaherpesvirus in a natural host.

ABSTRACT: Murine gammaherpesvirus 68 (MHV-68) infection of laboratory mice (Mus musculus) is an established model of gammaherpesvirus pathogenesis. The fact that M. musculus is not a host in the wild prompted us to reassess MHV-68 infection in wood mice (Apodemus sylvaticus), a natural host. Here, we report significant differences in MHV-68 infection in the two species: (i) following intranasal inoculation, MHV-68 replicated in the lungs of wood mice to levels approximately 3 log units lower than in BALB/c mice; (ii) in BALB/c mice, virus replication in alveolar epithelial cells was accompanied by a diffuse, T-cell-dominated interstitial pneumonitis, whereas in wood mice it was restricted to focal granulomatous infiltrations; (iii) within wood mice, latently infected lymphocytes were abundant in inducible bronchus-associated lymphoid tissue that was not apparent in BALB/c mice; (iv) splenic latency was established in both species, but well-delineated secondary follicles with germinal centers were present in wood mice, while only poorly delineated follicles were seen in BALB/c mice; and, perhaps as a consequence, (v) production of neutralizing antibody was significantly higher in wood mice. These differences highlight the value of this animal model in the study of MHV-68 pathogenesis.

SUBMITTER: Hughes DJ

PROVIDER: S-EPMC2849519 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Pathogenesis of a model gammaherpesvirus in a natural host.

Hughes David J DJ Kipar Anja A Sample Jeffery T JT Stewart James P JP

Journal of virology 20100203 8

Murine gammaherpesvirus 68 (MHV-68) infection of laboratory mice (Mus musculus) is an established model of gammaherpesvirus pathogenesis. The fact that M. musculus is not a host in the wild prompted us to reassess MHV-68 infection in wood mice (Apodemus sylvaticus), a natural host. Here, we report significant differences in MHV-68 infection in the two species: (i) following intranasal inoculation, MHV-68 replicated in the lungs of wood mice to levels approximately 3 log units lower than in BALB/ ...[more]

PMID: 20130062

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Project description:UnlabelledGammaherpesviruses, including Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV, or HHV-8), and murine gammaherpesvirus 68 (MHV68, γHV68, or MuHV-4), are B cell-tropic pathogens that each encode at least 12 microRNAs (miRNAs). It is predicted that these regulatory RNAs facilitate infection by suppressing host target genes involved in a wide range of key cellular pathways. However, the precise contribution that gammaherpesvirus miRNAs make to viral life cycle and pathogenesis in vivo is unknown. MHV68 infection of mice provides a highly useful system to dissect the function of specific viral elements in the context of both asymptomatic infection and disease. Here, we report (i) analysis of in vitro and in vivo MHV68 miRNA expression, (ii) generation of an MHV68 miRNA mutant with reduced expression of all 14 pre-miRNA stem-loops, and (iii) comprehensive phenotypic characterization of the miRNA mutant virus in vivo. The profile of MHV68 miRNAs detected in infected cell lines varied with cell type and did not fully recapitulate the profile from cells latently infected in vivo. The miRNA mutant virus, MHV68.Zt6, underwent normal lytic replication in vitro and in vivo, demonstrating that the MHV68 miRNAs are dispensable for acute replication. During chronic infection, MHV68.Zt6 was attenuated for latency establishment, including a specific defect in memory B cells. Finally, MHV68.Zt6 displayed a striking attenuation in the development of lethal pneumonia in mice deficient in IFN-γ. These data indicate that the MHV68 miRNAs may facilitate virus-driven maturation of infected B cells and implicate the miRNAs as a critical determinant of gammaherpesvirus-associated disease.ImportanceGammaherpesviruses such as EBV and KSHV are widespread pathogens that establish lifelong infections and are associated with the development of numerous types of diseases, including cancer. Gammaherpesviruses encode many small noncoding RNAs called microRNAs (miRNAs). It is predicted that gammaherpesvirus miRNAs facilitate infection and disease by suppressing host target transcripts involved in a wide range of key cellular pathways; however, the precise contribution that these regulatory RNAs make to in vivo virus infection and pathogenesis is unknown. Here, we generated a mutated form of murine gammaherpesvirus (MHV68) to dissect the function of gammaherpesvirus miRNAs in vivo. We demonstrate that the MHV68 miRNAs were dispensable for short-term virus replication but were important for establishment of lifelong infection in the key virus reservoir of memory B cells. Moreover, the MHV68 miRNAs were essential for the development of virus-associated pneumonia, implicating them as a critical component of gammaherpesvirus-associated disease.

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Pathogenesis of a model gammaherpesvirus in a natural host.

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Pathogenesis of a model gammaherpesvirus in a natural host.

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