Decoding Host Immunometabolic Control of Viral Persistence for Zoonotic Pathogens

PROJECT SUMMARY The threat of zoonoses has emerged as a critical problem for global health in the 21st century. Recent pandemics have underscored the urgent need to proactively develop more effective strategies to predict, prevent, and respond to the inevitable spillover of viruses from animals to humans. These viruses, carried by reservoir species such as bats, rodents, birds, and arthropod vectors, often are nonpathogenic in their natural hosts. However, upon spillover to the incidental human host, the consequences can be devastating and lead to outbreaks with significant health and economic impacts. One key to mitigating this risk lies in understanding why these viruses remain relatively benign in their reservoir hosts but can cause severe disease in humans. As a trainee scientist, I have interrogated both host- and viral-determinants of pathogenesis of multiple pathogens of pandemic potential. My research has uncovered key virologic, immunologic, and metabolic factors underpinning viral infection outcomes in the human host and natural reservoir species. Thus far, in Phase I of these studies, my work has answered long-standing questions in the fields of virology and disease ecology by linking the production of defective interfering particles (DIPs) with the establishment of nonpathogenic, life-long infection in a neonatal mouse model of arenavirus persistency. DIPs, and the related defective viral genomes (DVGs), are unique components of the viral population that are replication-deficient on their own yet can interfere with the production of standard infectious virus. However, viruses alone are only one piece of the host-virus relationship. Further understanding of the host contribution to the establishment of persistency in reservoir hosts is needed. In Phase II, I will develop an independent research program that bridges laboratory- based investigation into the immune mechanisms underlying the establishment and maintenance of viral persistency and field-based translation of these findings into the bona fide reservoir host. This proposal will specifically address 1) the DIP-specific immune signatures in acutely infected rodents in a continuation of Phase I studies, 2) the metabolic status of persistently infected wild Mus as a transitional research project and finally 3) the immunometabolic regulation of persistency in laboratory models of generational viral infection as an independent research direction. Successfully completing these aims will offer new insights into the fundamental aspects of viral and host biology that drive non-pathogenic, persistent infections in reservoir species. Future research will focus on understanding how this immunometabolic regulation becomes disrupted during acute infections in incidental human hosts and will be expanded to other viral families and host species. This work will contribute to a growing career that integrates virology, immunology, and reservoir biology, with the long-term aim of developing effective therapies for high-priority pathogens with pandemic potential.