Abstract
Murine γ-herpesvirus 68 (MHV-68) infection of Mus musculus-derived strains of mice is an attractive model of γ-herpesvirus infection. Surprisingly, however, ablation of expression of MHV-68 M3, a secreted protein with broad chemokine-binding properties in vitro, has no discernable effect during experimental infection via the respiratory tract. Here we demonstrate that M3 indeed contributes significantly to MHV-68 infection, but only in the context of a natural host, the wood mouse (Apodemus sylvaticus). Specifically, M3 was essential for two features unique to the wood mouse: virus-dependent inducible bronchus-associated lymphoid tissue (iBALT) in the lung and highly organized secondary follicles in the spleen, both predominant sites of latency in these organs. Consequently, lack of M3 resulted in substantially reduced latency in the spleen and lung. In the absence of M3, splenic germinal centers appeared as previously described for MHV-68-infected laboratory strains of mice, further evidence that M3 is not fully functional in the established model host. Finally, analyses of M3's influence on chemokine and cytokine levels within the lungs of infected wood mice were consistent with the known chemokine-binding profile of M3, and revealed additional influences that provide further insight into its role in MHV-68 biology.
Highlights
The human c-herpesviruses - Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV; alternatively human herpesvirus 8 [HHV-8]) - possess significant oncogenic potential, in the setting of immune deficiency
The titer of virus produced in the lungs of wood mice, is substantially lower, though the long-term viral DNA loads established within the lung of wood and BALB/c mice are equivalent [22]
We have shown that the Murine c-herpesvirus 68 (MHV-68) M3 gene, which encodes a highly expressed chemokine-binding protein [15,16], contributes substantially to infection in the lung and spleen of wood mice (Apodemus sylvaticus), which we have conclusively shown to be a natural host of MHV-68 [21]
Summary
The human c-herpesviruses - Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV; alternatively human herpesvirus 8 [HHV-8]) - possess significant oncogenic potential, in the setting of immune deficiency. Both establish lifelong latent infections, primarily within B lymphocytes, through the actions of a limited repertoire of their approximately 90 genes. Much of the effort to define the biology of MHV-68 infection and its applicability as a model of human cherpesvirus infections, has focused on the roles of these genes in the context of infection within inbred strains of laboratory mice. Of the proteins encoded by this locus, the biochemical function of M3 is the best understood
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