The magnitude and duration of vertebrate viremia is a critical determinant of arbovirus transmission, geographic spread, and disease severity. We find that multiple alphaviruses, including chikungunya (CHIKV), Ross River (RRV), and o'nyong 'nyong (ONNV) viruses, are cleared from the circulation of mice by liver Kupffer cells, impeding viral dissemination. Clearance from the circulation was independent of natural antibodies or complement factor C3, and instead relied on scavenger receptor SR-A6 (MARCO). Remarkably, lysine to arginine substitutions at distinct residues within the E2 glycoproteins of CHIKV and ONNV (E2 K200R) as well as RRV (E2 K251R) allowed for escape from clearance and enhanced viremia and dissemination. Mutational analysis revealed that viral clearance from the circulation is strictly dependent on the presence of lysine at these positions. These findings reveal a previously unrecognized innate immune pathway that controls alphavirus viremia and dissemination in vertebrate hosts, ultimately influencing disease severity and likely transmission efficiency.
All data generated or analysed during this study are included in the manuscript and supporting files.
Tabula Muris: Transcriptomic characterization of 20 organs and tissues from Mus musculus at single cell resolutionGene Expression Omnibus, GSE109774.
- Thomas E Morrison
- Kathryn S Carpentier
- Kathryn S Carpentier
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#00026) of the University of Colorado School of Medicine (Assurance Number A3269-01). Experimental animals were humanely euthanized at defined endpoints by exposure to isoflurane vapors followed by thoracotomy.
- John W Schoggins, University of Texas Southwestern Medical Center, United States
© 2019, Carpentier et al.
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