MOLECULAR DETERMINANTS OF HEPATITIS C VIRUS SPECIES TROPISM

Abstract

Communicable diseases, including infectious disease, remained the second highest contributor to the total number of disability adjusted life-years (DALYs) lost in 2017 (more than 17% of the 2.5 billion DALYs) (1). The pathogens responsible for these diseases are a diverse array of viruses, bacteria and parasites, each with varying tropism, i.e. the propensity of a given pathogen to infect a particular cell type, tissue and/or species. At the level of species tropism, some pathogens are more promiscuous than others, infecting a broad range of vertebrates and invertebrates (e.g. the bacterium Salmonella enterica) while on the opposite end of the spectrum are pathogens with highly restricted tropism limited to only humans or humans and select non-human primate (NHP) species (e.g. hepatitis C virus, HCV). It is the latter category of pathogens that are most problematic for researchers as their very nature hinders study in traditional small animal models, such as mice. Thus, to facilitate such work, it is crucial to identify the determinants of tropism, which at the molecular level can be due to: (i) necessary factors missing or the ortholog of such a factor being incompatible in a given species, such as receptors for a specific virus; (ii) the presence of dominant restriction factors that block steps of the pathogen’s life cycle, such as its replication within host cells; (iii) the varying abilities of a pathogen to evade and/or disrupt the immune response of a given host. The following dissertation describes telling examples of these determinants, specifically for RNA viruses infecting humans, and how knowledge of such factors is important in generating improved research models as well as in understanding emergent and re-emergent pathogens. This work provides novel insights concerning the impact of cyclophilin A on HCV host tropism and the conservation of innate immune responses observed across diverse NHP species, with implications for the development of a small, immunocompetent animal model for HCV and related pathogens.