Chikungunya virus (CHIKV) is an emerging mosquito-transmitted alphavirus that causes an abrupt onset of fever with severe joint and muscle pain. In a significant number of patients chronic and debilitating arthritis can persists for months to years, with recent epidemiological projections suggesting there are 400,000 patients in the Western Hemisphere with chronic CHIKV arthritis. The pathogenesis of CHIKV arthritis is poorly understood. Evidence from humans, non-human primates, and mouse studies suggest that CHIKV replicates within the joint tissue and muscle cells and that persistent viral RNA can be detected long after acute infection is cleared. However, due to technical limitations, the cells harboring this viral RNA have not been identified and how they contribute to disease is unclear. In preliminary data we have engineered a recombinant CHIKV virus to express Cre recombinase and we have shown that this virus establishes chronic infection, including persistent RNA. When this virus was used to infect tdTomato reporter mice we found marked cells that persisted even after replicating virus has been cleared. In this proposal we will use this novel system to begin to ask several questions including: 1) which cell types are infected by CHIKV and which ones harbor persistent viral RNA?; 2) what is the sequence of the RNA that persists and why does it not result in productive replication?; 3) are the cell types that survive CHIKV infection transcriptionally altered?; and 4) do the cells that survive CHIKV infection contribute to disease pathogenesis? Overall, our studies will provide important insight into the pathogenesis of chronic CHIKV arthritis and may direct efforts toward the development of future therapeutics.

Public Health Relevance

Chikungunya virus is a mosquito-transmitted alphavirus that causes persistent, debilitating polyarthritis in a significant numbers of patients. While persistent viral RNA has been detected in both patients and animal models, no replicating virus has been detected. Our goal is to develop the tools that will allow us to identify cells that were infected by CHIKV, to determine why viral RNA but not replicating virus persists, and to gain a better understanding of what drives chronic arthralgias and arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI135490-02
Application #
9618851
Study Section
Virology - B Study Section (VIRB)
Program Officer
Repik, Patricia M
Project Start
2018-01-02
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130