Role of a novel human-virus chimeric protein generated by upstream translation and genetic overprinting

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SUMMARY The capacity of a pathogen to overcome host barriers and establish infection is based on the expression of pathogen-derived proteins. To understand how a pathogen antagonizes the host and establishes infection, we need to have a clear understanding of what proteins a pathogen encodes, how they function, and in what manner they contribute to virulence. The current dogma about many life-threatening pathogens is that they encode just a handful of proteins because of their limited genome. RNA viruses, like Influenza A virus (IAV), are a prime example of this paradigm. Based on this, our understanding of virus life cycles, pathogenesis, and therapeutic or prophylactic methods of disease containment are limited to a small set of known proteins encoded by the viral genome. We hypothesized that, as a result of host-virus genetic interaction, RNA viruses could generate chimeric host-virus genes that are translated into proteins during infection. In fact, IAV, and many other highly pathogenic viruses, use short host RNAs to prime viral transcription to generate viral mRNA. Thus, we further hypothesized that start codons within host primer sequences could drive the expression of chimeric human-viral coding sequences, a process that would depend on the translatability of the viral UTR sequences. Our recent publication indicates the existence of this mechanism, which creates human-virus protein chimeras either as extensions of canonical viral proteins or novel polypeptides by genetic overprinting. This idea is supported by evolutionary analysis and functional data in a few preliminary case studies. The goal of this exploratory R21 application is to characterize in detail the genomic context that allows the generation of viral-human proteins along with characterizing, in a physiological manner, the role of a conserved human-virus protein generated by IAV. A combination of reserve genetic approaches will be used to generate viral mutants and to fully characterize their virulence at the cellular and organismal level. By investigating the role of unknown pathogen- derived proteins, this proposal has the potential to establish their importance, elucidate their role during infection, and provide a proof-of-principle study for future virology- immunology- and genomic studies aimed at defining host-virus proteins in the multiple virus in which they can be generated (3 viral families comprising human, other animal and plant viruses).