Although natural killer (NK) cells are best known for their capacity to kill tumor cells in a perforin-dependentmanner, recent studies have also indicated an important role for NK cells in innate immunity to pathogens,especially viruses. In prior work, the applicant's laboratory has elucidated the basis for genetic resistance ofcertain strains of mice to murine cytomegalovirus (MCMV). This is due to a genetic locus in the NK genecomplex (NKC) for an NK cell activation receptor that recognizes an MCMV encoded ligand. In vitro and invivo studies have revealed two phases of NK cell responses during MCMV infection, a 'non-specific' earlyphase followed by selective proliferation of NK cells bearing the relevant activation receptor. Available datafrom the literature and the applicant's laboratory strongly suggest that mouse NK cell responses topoxviruses (ectromelia virus, vaccinia virus) are highly related to their responses to MCMV, and involve boththe non-specific early phase and a specific phase involving another NK cell activation receptor encoded inthe NKC. Therefore, the applicant proposes the following specific aims to study: 1) The basiccharacteristics of the NK cell response to poxviruses; 2) Specific NK cell receptor triggering; 3) The role ofNKG2D in poxvirus infections; and 4) Innate immune evasion by poxviruses. These studies will provideunique insight into the innate NK cell immune response to poxviruses.
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