image: Representative image of frozen section of whole ankle taken at 28 days post infection from reporter mice (tdTomato mice) infected with 106 PFU CHIKV-3?-Cre. Blue shows DAPI staining and red shows tdTomato. The tdTomato cells survive CHIKV infection and harbor the persistent CHIKV RNA. Scale bar represents 1000 ?m. view more
Credit: Young AR, et al. (2019)
A new method for permanently marking cells infected with chikungunya virus could reveal how the virus continues to cause joint pain for months to years after the initial infection, according to a study published August 29 in the open-access journal PLOS Pathogens by Deborah Lenschow of Washington University School of Medicine in St. Louis, and colleagues. According to the authors, uncovering the mechanisms for long-term disease could aid in the development of treatments and preventative measures for this incapacitating, virally induced chronic arthritis.
Chikungunya virus is spread by mosquitoes and causes severe joint and muscle pain. Approximately 30 to 60 percent of people infected with the virus continue to experience joint pain for months to years after the initial infection. However, the cause of this persistent joint pain is unclear, as replicating virus cannot be detected during the chronic phase. To address this question, Lenschow and colleagues developed a reporter system to permanently mark cells infected by chikungunya virus.
Using this system, they show in mice that marked cells surviving chikungunya virus infection are a mixture of muscle and skin cells that are present for at least 112 days after initial virus inoculation. Treatment of mice with an antibody that blocks chikungunya virus infection reduces the number of marked cells in the muscle and skin. Moreover, surviving marked cells contain most of the persistent chikungunya virus RNA. Taken together, the findings provide further evidence for musculoskeletal cells as targets of chikungunya virus infection in the acute and chronic stages of disease. According to the authors, this reporter system represents a useful tool for identifying and isolating cells that harbor chronic viral RNA in order to study the mechanisms underlying chronic disease.
"Persistent CHIKV RNA can be detected in human and animal models but no one has been able to identify where the RNA resides due to insensitive techniques," adds Lenschow. "Using our reporter system we have demonstrated that cells can survive CHIKV infection, and these cells harbor most of the persistent RNA. Since many believe that this persistent RNA contributes to chronic arthritis, this system will be a useful tool to study the mechanisms underlying chronic disease."
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Research Article
Funding: ARY was supported by a NIGMS Cellular, Biochemical, and Molecular (CMB) Sciences Predoctoral Research Training Grant (T32 GM007067, https://www.nigms.nih.gov/). LEC was supported by an NIH Postdoctoral Research Training Grant (T32 CA009547, https://www.nih.gov/). DJV was supported by the NIH (R01 AR070030 and R21 AR073507), as well as Shriners Hospitals for Children - St. Louis (85117, https://www.shrinershospitalsforchildren.org/st-louis). MSD was supported by the NIH (R01 AI143673 and R01AI123348). DJL was supported by the NIH (R01 A1127513 and R21 A1135490). Additionally, the Washington University Musculoskeletal Research Center received funding from the NIH (P30 AR057235), and the Washington University Center for Cellular Imaging was supported by the Washington University Rheumatic Diseases Research Resource-based Center funded by the NIH (P30 AR073752, http://grantome.com/grant/NIH/P30-AR073752-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: MSD is a consultant for Inbios and on the Scientific Advisory Board of Moderna, and has filed a provisional patent on Mxra8 antibodies and related proteins.
Citation: Young AR, Locke MC, Cook LE, Hiller BE, Zhang R, Hedberg ML, et al. (2019) Dermal and muscle fibroblasts and skeletal myofibers survive chikungunya virus infection and harbor persistent RNA. PLoS Pathog 15(8): e1007993. https://doi.org/10.1371/journal.ppat.1007993
Author Affiliations:
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America
Shriners Hospitals for Children-St. Louis, St. Louis, Missouri, United States of America
In your coverage please use this URL to provide access to the freely available paper: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007993
Journal
PLoS Pathogens