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Isolation and Quantification of Zika Virus from Multiple Organs in a Mouse
Published on: August 15, 2019
Chikungunya virus persists in joint-associated macrophages and promotes chronic disease
Thomas Morrison1, Kristen Zarrella2, Ryan Sheridan1
1Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora, CO, USA.
Abstract:
Arthritogenic alphaviruses including chikungunya, Mayaro, and Ross River viruses cause long-lasting musculoskeletal pain and inflammation. However, mechanisms driving chronic disease remain poorly understood. Here, we investigated joint-associated tissues in alphavirus-infected mice at a late stage of infection. Utilizing scRNA-seq, spatial transcriptomics, and flow cytometry we identified an accumulation of inflammatory macrophages in joint-associated tissues with elevated Tnf, Nlrp3, Il1b, and H2-Aa expression, and these cells harbored CHIKV RNA. Moreover, we identified an accumulation of CD4+ T cells in joint-associated tissues, which express Ifng. Depletion of CD4+ T cells diminished MHC-II expression on joint macrophages, highlighting their potential role in inflammation. In addition, treatment with a small molecule inhibitor of CHIKV replication during chronic disease reduced viral RNA and joint inflammation, suggesting that viral RNA replication promotes chronic joint disease. Our data suggest that macrophages harbor replicating viral RNA and contribute to the sustained joint inflammation associated with chronic alphavirus disease.
Insights
Chronic alphavirus infection causes joint inflammation. Inflammatory macrophages harbor viral RNA, contributing to sustained pain and inflammation. Targeting viral replication may reduce chronic disease.
Area of Science:
- Virology
- Immunology
- Rheumatology
Background:
- Arthritogenic alphaviruses cause persistent musculoskeletal pain and inflammation.
- Mechanisms underlying chronic alphavirus-induced joint disease are not fully understood.
Purpose of the Study:
- Investigate the cellular and molecular mechanisms driving chronic joint inflammation in alphavirus-infected mice.
- Identify key cellular players and pathways involved in sustained joint pathology.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) of joint-associated tissues.
- Spatial transcriptomics and flow cytometry.
- In vivo CD4+ T cell depletion and CHIKV replication inhibition.
Main Results:
- Accumulation of inflammatory macrophages expressing TNF, NLRP3, IL1B, and MHC-II in chronic alphavirus infection.
- Macrophages harbored CHIKV RNA, suggesting active viral replication.
- CD4+ T cells accumulated and influenced macrophage MHC-II expression.
- Inhibiting CHIKV replication reduced viral RNA and joint inflammation.
Conclusions:
- Macrophages harbor replicating alphavirus RNA and contribute to chronic joint inflammation.
- Viral RNA replication is a key driver of sustained joint disease.
- CD4+ T cells play a role in modulating macrophage-driven inflammation.
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