Respiratory syncytial virus (RSV) bronchiolitis is a leading cause of infant hospitalization and mortality. We previously identified that prostaglandin D2 (PGD2), released following RSV infection of primary human airway epithelial cells or pneumonia virus of mice (PVM) infection of neonatal mice, elicits pro- or antiviral innate immune responses as a consequence of D-type prostanoid receptor 2 (DP2) or DP1 activation, respectively. Here, we sought to determine whether treatment with the DP1 agonist BW245c decreases the severity of bronchiolitis in PVM-infected neonatal mice. Consistent with previous findings, BW245c treatment increased IFN-λ production and decreased viral load in week 1 of the infection. However, unexpectedly, BW245c treatment increased mortality in week 2 of the infection. This increased morbidity was associated with viral spread to the parenchyma, an increased cellular infiltrate of TNF-α-producing cells (neutrophils, monocytes, and CD4⁺ T cells), and the heightened production of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. These phenotypes, as well as the increased mortality, were significantly attenuated following the administration of anti-TNF-α to PVM-infected, BW245c-treated mice. In summary, pharmacological activation of the DP1 receptor in PVM-infected neonatal mice boosts antiviral innate and adaptive immunity, however, this is ultimately detrimental, as a consequence of increased TNF-α-induced morbidity and mortality.

呼吸道合胞病毒 (RSV) 细支气管炎是婴儿住院和死亡的主要原因。我们之前发现前列腺素 D2 (PGD2) 在 RSV 感染原代人气道上皮细胞或小鼠肺炎病毒 (PVM) 感染新生小鼠后释放，由于 D 型前列腺素受体而引发促病毒或抗病毒先天免疫反应2 (DP2) 或 DP1 分别激活。在这里，我们试图确定用 DP1 激动剂 BW245c 治疗是否会降低 PVM 感染的新生小鼠毛细支气管炎的严重程度。与之前的发现一致，BW245c 治疗在感染的第 1 周增加了 IFN-λ 的产生并降低了病毒载量。然而，出乎意料的是，BW245c 治疗增加了感染第 2 周的死亡率。⁺ T 细胞），以及促炎细胞因子 TNF-α、IL-6 和 IL-1β 的产生增加。这些表型以及死亡率增加在向 PVM 感染、BW245c 处理的小鼠施用抗 TNF-α 后显着减弱。总之，PVM 感染的新生小鼠中 DP1 受体的药理学激活增强了抗病毒先天免疫和适应性免疫，然而，由于 TNF-α 诱导的发病率和死亡率增加，这最终是有害的。