Immune Modulation to Improve Survival of Viral Pneumonia in Mice

Abstract

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 Sendai paramyxovirus 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 Sendai virus 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.

Epithelial Immunomodulation by Aerosolized Toll-like Receptor Agonists Attenuates Allergic Responsiveness in Mice

“…11 More recently, we showed that Pam2ODN can attenuate chronic asthma-like lung disease in mice infected with Sendai virus (SeV). 12 We reasoned that Pam2ODN would exert a protective effect against the chronic disease by reducing the viral burden in the acute infection, but we observed some efficacy when Pam2ODN treatment was given at remote time points when the virus burden was not reduced in the acute infection. This partial discordance between the reduction in viral burden and chronic disease severity led us to hypothesize that Pam2ODN also modulated the type 2 immune response that drives the chronic disease.…”

Innate immune responses in pneumonia

“…TLR binding and signaling has been reviewed in detail recently [ 28 ], thus the focus here will be on recent advances during lung infection. Administration of a cocktail of TLR agonists (Pam2-ODN, TLR2/6 and 9 agonists) during Sendai paramyxovirus infection leads to alleviation of lung epithelial damage early in infection, reduced viral burden and decreased mouse mortality [ 30 ]. In an observational study, elderly patients with severe pneumonia exhibited lower levels of monocyte TLR2 and TLR4 expression, correlating with diminished serum concentrations of interleukin-1 (IL-1), interleukin-6 (IL-6), and TNF-α [ 31 ].…”

Response of Lung Microbiota to Changes of Pulmonary Innate Immunity under Healthy Conditions

“…An important question that needs to be addressed is why the lungs of mice were harvested six days after exposure to Pam2-ODN, a toll-like receptor agonist. Inhalation of Pam2-ODN has been shown to protect mice infected with virus or bacteria few hours after exposure to the toll-like receptor agonist (2)(3)(4). Therefore, it is conceivable that earlier evaluation of lung microbiota would have provided different results.…”