Immune modulation to improve survival of respiratory virus infections in mice

Abstract

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.

Modulation of the Innate Immune Response by Targeting Toll-like Receptors: A Perspective on Their Agonists and Antagonists

“…Moreover, a therapeutic role for TLR5 has been proposed very recently by Chakraborty et al; it can be used as an immunomodulator that is able to activate the immune system to fight the SARS-CoV-2 . Interestingly, in a 2020 preprint research article, the use of a combination of inhaled 1a and CpG-ODNs in mice to stimulate their immune system against SARS-CoV-2 has been reported . For these reasons, a wider exploration of TLRs and their modulators may drive the discovery of new potential drugs or vaccine adjuvants to be applied against SARS-CoV-2.…”

“…320 Interestingly, in a 2020 preprint research article, the use of a combination of inhaled 1a and CpG-ODNs in mice to stimulate their immune system against SARS-CoV-2 has been reported. 321 For these reasons, a wider exploration of TLRs and their modulators may drive the discovery of new potential drugs or vaccine adjuvants to be applied against SARS-CoV-2. As recently reported by Conti et al, the binding of SARS-CoV-2 to TLR2, TLR3, or TLR4 determines the release of inflammatory cytokines such as IFN-α, TNF, and IL-1.…”

Novel and Evolving Therapies for COVID-19 Related Pulmonary Complications,

“…50 51 The PUL-042 showed satisfactory defense against a broad range of pulmonary pathogens, including the coronaviruses that cause MERS and SARS in pre-clinical mice models. 52 Moreover, PUL-042 can reduce the viral load in the pulmonary airways post-infection. 52 Based on this preliminary study, Pulmotect, Inc. (Houston, USA) started clinical trials i.e.…”

“…52 Moreover, PUL-042 can reduce the viral load in the pulmonary airways post-infection. 52 Based on this preliminary study, Pulmotect, Inc. (Houston, USA) started clinical trials i.e. NCT04313023 and NCT04312997 to prevent COVID-19.…”

Immune Modulation to Improve Survival of Viral Pneumonia in Mice

“…Some of the results of these studies have been previously reported in the form of a preprint ( 23 ).…”