Defining Human Skin Immunity to Culicoides Probing and Oropouche Virus Infection

About This Grant

Abstract Oropouche virus (OROV) is an emerging Orthobunyavirus of concern to human health throughout the Americas. To date, OROV is the only known human arthropod-borne virus primarily transmitted by Culicoides midges. The recent upsurge in OROV infections driven by a novel viral reassortant, coupled with the geographical spread and the detection of more severe outcomes makes OROV an important threat to global health. Currently, there are significant limitations in our understanding of the epidemiology, ecology, and pathogenesis of OROV and its reassortants. This knowledge gap is particularly pronounced regarding vector-virus-host interactions that enable OROV to infect and disseminate in human skin, the critical organ for virus transmission. To address this gap, we will leverage a robust human skin model of arbovirus infection to define the cutaneous immunologic events during Culicoides probing and its impact on OROV replication and spread in human skin. This research proposal is in direct response to NIH Notice of Special Interest NOT-AI-24-048: “Immune Responses to Arthropod Feeding on Vertebrate Hosts”. Aim 1 will define the physiological effects of Culicoides probing in human skin immune response. Aim 2 will provide a comparative analysis between historical and contemporary OROV strains to pinpoint the contribution of Culicoides probing to cellular tropism, cutaneous immune responses, and viral dissemination. Our transdisciplinary and highly collaborative research team brings together unique strengths in cutaneous immunity of arboviruses (Priscila Da Silva Castanha), biology and ecology of Culicoides (Stacey Scroggs and Bethany McGregor), and bunyavirology (Cynthia McMillen). Our studies will address fundamental questions about the intricate interplay between the early host response to Culicoides probing and viral infection that are central to successful OROV transmission. This knowledge is pivotal for the development of therapeutic strategies and interventions against this neglected pathogen.