The novel innate immune-antagonistic effects of the multifunctional ectromelia virus C15 protein

Abstract

Abstract The success of poxviruses as pathogens depends upon their extensive antagonism of host immune responses by a large arsenal of immunomodulatory proteins. The C15 protein of ectromelia virus (ECTV, the agent of mousepox) is the largest of the ECTV immunomodulatory proteins and is a member of a well-conserved poxviral family previously studied as inhibitors of T cell activation. We have recently determined that C15 also facilitates early viral spread in vivo, suggesting a second non-adaptive function of C15. Accordingly, we sought to further investigate this new function and identify the cellular target. We first found that C15 maintains its replication-promoting effect in RAG KO but not RAG IL2RG double KO mice, implying the targeting of NK cells. Nevertheless, the impact of C15 is drastically less in RAG KO than WT mice, suggesting that C15 also targets a RAG-dependent immune component. Further studies in various immune deficient strains implicate type I and III interferons, perforin and the NK gene complex in this novel function. The results prompt further in vitro and in vivo studies into the impact of C15 on NK cell and γδ T cell function, as the RAG-independent and -dependent targets respectively, and lead us to propose that, unique among currently identified viral virulence factors, C15 selectively antagonizes both the adaptive and innate immune responses.