Immune Modulation to Improve Survival of Viral Pneumonia in Mice

• Published in: American journal of respiratory cell and molecular biology Vol. 63; no. 6; pp. 758 - 766
• Main Authors: Wali, Shradha, Flores, Jose R., Jaramillo, Ana M., Goldblatt, David L., Pantaleón García, Jezreel, Tuvim, Michael J., Dickey, Burton F., Evans, Scott E.
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.12.2020
• Subjects: Adaptive immunity; Agonists; Animals; CD8 antigen; Coronaviruses; COVID-19; Epithelial Cells - drug effects; Epithelial Cells - immunology; Epithelial Cells - virology; Female; Immune response; Immunity, Innate - drug effects; Immunity, Innate - immunology; Immunomodulation; Innate immunity; Internalization; Lipopeptides - pharmacology; Lung - drug effects; Lung - immunology; Lung - virology; Lymphocytes T; Mice; Mice, Inbred C57BL; Mortality; Original Research; Pandemics; Pneumonia; Pneumonia - immunology; Pneumonia - pathology; Pneumonia - prevention & control; Pneumonia, Viral - drug therapy; Pneumonia, Viral - immunology; Pneumonia, Viral - virology; Public health; Respiratory diseases; Respirovirus Infections - drug therapy; Respirovirus Infections - immunology; Respirovirus Infections - virology; Sendai virus - drug effects; Sendai virus - immunology; Severe acute respiratory syndrome coronavirus 2; Toll-like receptors; Viral Load - drug effects; immunomodulation; CD8+ T cells; immunopathology; inducible epithelial resistance; viral pneumonia
• ISSN: 1044-1549; 1535-4989; 1535-4989
• DOI: 10.1165/rcmb.2020-0241OC

Viral pneumonias remain global health threats, as exemplified in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, requiring novel treatment strategies both early and late in the disease process. We have reported that mice treated before or soon after infection with a combination of inhaled Toll-like receptor (TLR) 2/6 and 9 agonists (Pam2-ODN) are broadly protected against microbial pathogens including respiratory viruses, but the mechanisms remain incompletely understood. The objective of this study was to validate strategies for immune modulation in a preclinical model of viral pneumonia and determine their mechanisms. Mice were challenged with the in the presence or absence of Pam2-ODN treatment. Virus burden and host immune responses were assessed to elucidate Pam2-ODN mechanisms of action and to identify additional opportunities for therapeutic intervention. Enhanced survival of pneumonia with Pam2-ODN treatment was associated with reductions in lung virus burden and with virus inactivation before internalization. We noted that mortality in sham-treated mice corresponded with CD8 T-cell lung inflammation on days 11-12 after virus challenge, after the viral burden had declined. Pam2-ODN blocked this injurious inflammation by minimizing virus burden. As an alternative intervention, depleting CD8 T cells 8 days after viral challenge also decreased mortality. Stimulation of local innate immunity within the lungs by TLR agonists early in disease or suppression of adaptive immunity by systemic CD8 T-cell depletion late in disease improves outcomes of viral pneumonia in mice. These data reveal opportunities for targeted immunomodulation to protect susceptible human subjects.