RT Journal Article
SR Electronic
T1 Immune modulation to improve survival of respiratory virus infections in mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.16.045054
DO 10.1101/2020.04.16.045054
A1 Shradha Wali
A1 Jose R. Flores
A1 Ana Maria Jaramillo
A1 David L. Goldblatt
A1 Jezreel Pantaleón García
A1 Michael J. Tuvim
A1 Burton F. Dickey
A1 Scott E. Evans
YR 2020
UL http://biorxiv.org/content/early/2020/04/18/2020.04.16.045054.abstract
AB Viral pneumonia remains a global health threat requiring novel treatment strategies, as strikingly exemplified in the SARS-CoV-2 pandemic of 2019-2020. We have reported that mice treated with a combination of inhaled Toll-like receptor (TLR) 2/6 and TLR 9 agonists (Pam2-ODN) to stimulate innate immunity are broadly protected against respiratory pathogens, but the mechanisms underlying this protection remain incompletely elucidated. Here, we show in a lethal paramyxovirus model that Pam2-ODN-enhanced survival is associated with robust virus inactivation by reactive oxygen species (ROS), which occurs prior to internalization by lung epithelial cells. However, we also found that mortality in sham-treated mice temporally corresponded with CD8+ T cell-enriched lung inflammation that peaks on days 11-12 after viral challenge, when the viral burden has waned to a scarcely detectable level. Pam2-ODN treatment blocked this injurious inflammation by reducing the viral burden, and alternatively, depleting CD8+ T cells 8 days after viral challenge also decreased mortality. These findings reveal opportunities for targeted immunomodulation to protect susceptible individuals against the morbidity and mortality of respiratory viral infections.Competing Interest StatementThe authors have declared no competing interest.