Out of the reservoir: identification and characterization of viral and host factors governing the pathobiology of zoonotic cowpox viruses

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This is a continuation proposal in which we build on results from the first funding period. Although we were able, for the first time, to isolate and characterize in detail a cowpox virus (CPXV) from the rodent reservoir, the common vole, we are continuing field studies. Our goal is to gain a better understanding of the ecology of CPXV maintenance and transmission within the reservoir, by screening for further isolates with an optimized sampling scheme and by determining seroprevalences in defined habitats. The first vole isolate allowed comparison with available CPXV sequences from accidental/spill-over hosts (rats, cats, cattle). Alterations in virus-encoded proteins were identified that we surmise allow CPXV maintenance in the reservoir and others that are responsible for successful spill-over into accidental hosts. We will here investigate if and how the identified CPXV factors contribute to maintenance in the natural vole reservoir and to spill-overs into different accidental hosts. Importantly, we shall determine how those factors are linked to virulence. The experiments will be done by first creating recombinant and chimeric CPXV that are based on full-length clones and by performing cell biological, biochemical and immunological assays to determine protein function. Among others, we will perform detailed experiments on potentially species-specific CPXV immune evasion proteins (e.g., 7tGP, CrmE and D7L proteins) as well on the possible interference of CPXV with Mx proteins in vole species. We shall cooperate with other groups of SPP1596 based on established cooperations, primarily R.G. Ulrich (screening of voles including prevalence studies), M. Marz (RNAseq analysis and automated annotation of CPXV genomes), K. Kramer-Schadt (ecology and modeling), G. Kochs (role of the vole Mx proteins) and C. Drosten (overall context of zoonotic rodent borne pathogens).