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.

病毒性肺炎仍然是全球健康威胁，例如严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 大流行，需要在疾病过程的早期和晚期采用新的治疗策略。我们报告说，在感染之前或之后不久，用吸入性 Toll 样受体 (TLR) 2/6 和 9 激动剂 (Pam2-ODN) 的组合治疗的小鼠可以广泛地保护免受包括呼吸道病毒在内的微生物病原体的侵害，但其机制仍未完全了解. 本研究的目的是验证病毒性肺炎临床前模型中免疫调节的策略并确定其机制。用仙台副粘病毒攻击小鼠在存在或不存在 Pam2-ODN 处理的情况下。对病毒负荷和宿主免疫反应进行了评估，以阐明 Pam2-ODN 的作用机制并确定治疗干预的其他机会。使用 Pam2-ODN 治疗提高仙台病毒肺炎的存活率与肺病毒负荷减少和内化前病毒灭活有关。我们注意到，在病毒负荷下降后，在病毒攻击后第 11-12 天，假治疗小鼠的死亡率与 CD8 ⁺ T 细胞肺部炎症相对应。Pam2-ODN 通过最大限度地减少病毒负担来阻止这种有害的炎症。作为替代干预，消耗 CD8 ⁺病毒攻击后 8 天的 T 细胞也降低了死亡率。在疾病早期通过 TLR 激动剂刺激肺内的局部先天免疫或在疾病晚期通过全身性 CD8 ⁺ T 细胞耗竭抑制适应性免疫可改善小鼠病毒性肺炎的结果。这些数据揭示了靶向免疫调节保护易感人类受试者的机会。