MHV68 Latency Modulates the Host Immune Response t

Authors: Fumitake Saito Toshihiro Ito Judith M Connett Matthew A Schaller William F Carson Cory M Hogaboam Rosemary Rochford Steven L Kunkel

Publish Date: 2013/06/27

Volume: 36, Issue: 6, Pages: 1295-1303

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Abstract

Murine gammaherpesvirus 68 MHV68 is a natural rodent pathogen that has been used as a model to study the pathogenesis of human gammaherpesviruses Like other herpesviruses MHV68 causes acute infection and establishes lifelong latency in the host Recently it has been shown that mice latently infected with MHV68 have resistance to unrelated pathogens in secondary infection models We therefore hypothesized that latent MHV68 infection could modulate the host response to influenza A virus To test this hypothesis mice were infected intranasally with influenza virus following the establishment of MHV68 latency Mice latently infected with MHV68 showed significantly higher survival to influenza A virus infection than did PBS mockinfected mice Latent MHV68 infection led to lower influenza viral loads and decreased inflammatory pathology in the lungs Alveolar macrophages of mice latently infected with MHV68 showed activated status and adoptive transfer of those activated macrophages into mice followed the infection with influenza A virus had significantly greater survival rates than control mice suggesting that activated alveolar macrophages are a key mechanistic component in protection from secondary infectionsHumans in a natural environment are exposed to multiple pathogens and face a constant risk of infection It has been demonstrated that in certain cases infection with one pathogen can affect the immune response to subsequent infection with nonrelated pathogens leading to “crossprotective immunity” or “heterologous immunity” 1 2 3 4 5 This protective effect has been shown between diverse pathogens including viruses bacteria and fungiGammaherpesviruses such as EpsteinBarr virus EBV are doublestranded DNA viruses that are important pathogens in humans and animals Most of the world’s population is latently infected with multiple herpesviruses however these infections are usually asymptomatic in immunocompetent persons Murine gammaherpesvirus 68 MHV68 is a natural pathogen of rodents that is closely related to the human gammaherpesviruses and has been used as a model to study the pathogenesis of human gammaherpesviruses 6 7 Also MHV68 has been shown to establish lifelong latency in B cells macrophages and dendritic cells in Balb/c mice 8 9Recently it has been shown that mice latently infected with MHV68 are protected against two nonrelated pathogens Listeria monocytogenes and Yersinia pestis and this protective effect is due in part to the activation of innate immunity and constitutive expression of interferon IFNgamma IFNγ that suppresses viral reactivation 10 These data suggested that “crossprotective immunity” may be a common phenomena but to date only a few pathogens have been studiedIn the present study we investigated whether MHV68 latency protects mice from lethal infection with influenza A virus a singlestranded RNA virus that causes acute respiratory infections that result in significant morbidity and mortality in humans and animals We evaluated the immunological response to influenza virus in PBS mockinfected and MHV68infected mice and further assessed the mechanisms underlying the increased survival seen in mice latently infected with MHV68Female Balb/c mice 6–8 weeks age The Jackson Laboratory were housed under specific pathogenfree conditions at the Unit for Laboratory Animal Medicine of the University of Michigan and treated in accordance with the guidelines of the animal ethical committee All experiments were done with the approval of the University of Michigan Committee for Use and Care of Animals UCUCAMHV68 strain WUMS and influenza A virus strain A/PR8/34 H1N1 isotype were obtained from the American Type Culture Collection To establish MHV68 latency mice were anesthetized and challenged intranasally with 4 × 104 PFU of MHV68 MHV68infected mice or with control PBS mockinfected mice Twentyeight 60 or 120 days following MHV68 or PBS challenge mice were infected intranasally with 1 × 104 PFU of influenza virus Whole lungs were harvested at the indicated times after influenza infectionIndividual excised lung lobes were inflated and fixed with 10  buffered formalin for morphometric analysis Sections of lung tissue were fixed in 4  neutral buffered paraformaldehyde embedded in paraffin and sectioned at 5micron thickness Sections were stained with hematoxylin and eosin

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