DP1 prostanoid receptor activation increases the severity of an acute lower respiratory viral infection in mice via TNF-α-induced immunopathology

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-lambda 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-alpha-producing cells (neutrophils, monocytes, and CD4(+) T cells), and the heightened production of the pro-inflammatory cytokines TNF-alpha, IL-6, and IL-1 beta. These phenotypes, as well as the increased mortality, were significantly attenuated following the administration of anti-TNF-alpha 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-alpha-induced morbidity and mortality.

Automated summary

In neonatal mice infected with PVM, treatment with the DP1 agonist BW245c increased IFN-lambda production and reduced viral load in the first week of infection. However, in the second week, BW245c treatment unexpectedly led to higher mortality, possibly due to viral spread, increased cellular infiltration, and elevated production of pro-inflammatory cytokines like TNF-alpha. Administering an anti-TNF-alpha antibody alleviated these effects, suggesting that pharmacological activation of DP1 receptor can boost antiviral immunity but may have detrimental consequences.