Mechanisms of simian arterivirus entry, immune evasion, and zoonotic potential

About This Grant

PROJECT SUMMARY/ABSTRACT Many emerging zoonotic viruses (animal viruses that transmit to humans) are highly pathogenic, having the potential to cause deadly epidemics or even global pandemics. The risks zoonotic viruses pose are highlighted by the emergence of the SARS/MERS coronaviruses, Ebola virus, and HIV-1, all of which are related to animal viruses that were unknown before they caused substantial cases of disease in humans. Given the risk animal viruses pose to humans, many researchers have turned to viral discovery—using genome sequencing tools and metagenomic analyses, researchers hope to identify novel animal viruses before they emerge in humans. We've developed a pipeline that integrates viral surveillance with molecular investigations in the laboratory to identify pre-emergent viruses with epidemic potential. Using this approach, we've provided compelling evidence suggesting that simian arteriviruses (SAVs)—understudied and neglected pathogens of African monkeys—are poised for spillover, posing a threat to human health. We demonstrate key biological features that poise SAVs for zoonosis, including: (1) compatibility with human receptors; (2) high titer propagation in human cells; and (3) potential for evasion of human innate immunity. Further interrogation of the biology of SAV infection is crucial for future epidemic preparedness efforts. The objective of this proposal is to uncover mechanisms of cell entry, immune evasion, and zoonotic potential for these highly concerning viral pathogens. In Aim 1, we employ a series of molecular, biochemical, structural, and functional approaches to define SAV-receptor interactions and establish proof-of-concept strategies for future therapeutics—an essential step in outbreak preparedness. In Aim 2, we will identify SAV proteins that antagonize the human innate immune response, with the goal of revealing vulnerabilities that may help develop safe and effective antiviral approaches. In Aim 3, we will thoroughly evaluate the zoonotic potential of diverse SAVs. This includes: (1) identifying novel SAVs through whole virome sequencing of wild African primate biomaterials; (2) the development and application of non-human primate induced-pluripotent stem cell (iPSC)-derived macrophages to isolate novel SAVs in cell targets from natural host species; and (3) detailed infection studies in human cells to evaluate human compatibility. Further, we will perform the first in-depth serosurvey for SAV exposure history using banked sera from a Ugandan case-control cohort. When taken together, this proposal will lead to a deeper understanding of the molecular biology and pathogenesis of these understudied viruses, as well as a greater appreciation for the zoonotic risk that they pose. It is imperative that we invest in characterizing the biology and pathogenesis of SAVs now so that we may begin to develop platform technologies (i.e., diagnostics, vaccines, therapeutics) in case they do emerge in the future.