Myeloid TLR2 signaling amplifies immunopathology in influenza-infected murine neonates.

We previously demonstrated that pretreatment with intranasal Lactobacillus rhammosus GG (LGG) prior to influenza viral (IAV) infection protected murine neonates through toll-like receptor (TLR) priming. Based on these results, we hypothesized that neonates had impaired TLR activation in response to IAV. However, translational studies with human neonatal monocytes stimulated with IAV exhibited comparable IL-6 production and sustained TLR2 expression compared to adults. Next, to further investigate the role of TLR2, transgenic mice lacking the TLR2 gene (TLR2-/-) were intranasally infected with IAV. TLR2-/- neonates displayed improved survival over C57BL/6 neonates after IAV infection, with reduced neutrophil recruitment at 6-days post-infection. To test the role of neutrophils in increasing mortality, neutrophil depletion was performed in C57BL/6 neonates; survival was improved. Additionally, treatment with an anti-TLR2 blocking antibody improved survival in the C57BL/6 neonates. Similarly, myeloid-specific TLR2-deficient mice demonstrated enhanced survival with improved histopathology and decreased neutrophil-associated pro-inflammatory cytokines and chemokines (IL-6, TNF-α, MCP-1, CXCL1), despite no changes in immune cell recruitment. Moreover, conditional knockout neonates did not amplify production of pro-inflammatory cytokines and chemokines from 3 days post-infection to 6-days post-infection, compared to the age-matched neonatal control group. These findings suggest that myeloid TLR2 signaling exacerbates neonatal susceptibility to respiratory viral infections by driving increased pulmonary inflammation over the first week of infection.