Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes epidemics of severe rheumatologic disease. The impact of CHIKV disease extends globally, with recent outbreaks occurring in Asia, Europe and the Americas. Up to 50% of patients report persistent rheumatologic symptoms, with incapacitating arthralgia lasting for months to years after infection. Chronic disease has been linked in humans and animal models with persistent CHIKV infection. Despite this, the host-viral interactions that dictate viral clearance or persistence are poorly defined. To identify adaptive mutations associated with chronic CHIKV infection, the Morrison laboratory isolated CHIKV from the circulation of a chronically-infected Rag1-/- mouse. This virus contained a mutation in the E2 glycoprotein (E2 K200R) that dramatically enhances viremia and viral dissemination in WT mice, leading to more severe disease outcomes. Moreover, introduction of an E2 K200R mutation into additional CHIKV strains or a closely related alphavirus, o'nyong nyong virus, also enhances viremia, demonstrating this mutation evades a host response that is operative against multiple alphaviruses. High viremia in humans and non-human primates infected with CHIKV has been associated with more severe acute disease and an increased potential for chronic disease. Therefore, this mutant virus provides a valuable tool to identify host and viral determinants of alphavirus dissemination and pathogenicity. The enhanced dissemination mediated by CHIKV E2 K200R (CHIKVE2 K200R) is independent of type I IFN, demonstrating that additional innate immune responses significantly contribute to CHIKV control. My preliminary data demonstrates that WT CHIKV particles are rapidly cleared from the circulation following intravenous inoculation, while CHIKVE2 K200R particles remain stably detectable. Depletion of phagocytic cells prevents clearance of WT CHIKV from the circulation, but has no impact on the circulating levels of CHIKVE2 K200R. These findings reveal a critical role for phagocytic cells in controlling WT CHIKV dissemination and suggest that CHIKVE2 K200R evades clearance by phagocytic cells. My objective is to define the phagocytic cells that are responsible for CHIKV clearance, and to define the viral determinants of clearance and escape. Based on my preliminary data, I hypothesize that splenic red pulp macrophages efficiently capture WT CHIKV, and that CHIKVE2 K200R evades this response by abrogating interactions with a conserved residue in the E1 glycoprotein, resulting in structural alterations that facilitate evasion of phagocytic cells.
In Aim 1, I will precisely define the population of phagocytic cells that mediate CHIKV clearance from the circulation.
In Aim 2, I will define viral determinants that mediate CHIKV clearance by phagocytic cells or escape of this clearance mechanism. The proposed research will significantly advance the field by defining new mechanisms of host control of alphavirus dissemination, and viral determinants of escape.

Public Health Relevance

Chikungunya virus is a mosquito-transmitted virus that causes large epidemics of acute and chronic joint pain and arthritis, and the capacity of the host to restrict chikungunya virus dissemination is an important determinant of disease outcomes. This project will define mechanisms by which host phagocytic cells restrict dissemination and mechanisms by which a single polymorphism in the viral attachment protein allows for viral evasion of this restriction. The knowledge gained from these studies may aid in the development of new treatments or vaccines against chikungunya virus infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI140567-03
Application #
10056971
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dupuy, Lesley Conrad
Project Start
2018-11-01
Project End
2021-06-30
Budget Start
2020-11-01
Budget End
2021-06-30
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045