C107-15 Respiratory Commensal Streptococcus Regulates Innate Immunity to Protect Against Influenza Infection

Rationale Respiratory microbial dysbiosis has been implicated in the onset and progression of community-acquired pneumonia (CAP). However, the dynamic variations in the respiratory microbiota and its interactions with the host immune response remain poorly understood. Methods Patients with CAP were enrolled, and respiratory, blood, and stool samples were collected at three time points: admission, 2-3 days later, and just before discharge. Integrative analysis of the respiratory and gut microbiomes with peripheral blood transcriptomics revealed the relationship between the microbiota and host immunity. Key bacteria were isolated and their interaction with influenza infection was validated using an animal model. Results We found that CAP patients exhibited disrupted sputum microbiota at the early, middle, and late stages of hospitalization. Pathways related to peptidoglycan biosynthesis and immune evasion, particularly those contributed by the Streptococcus genus, were enriched in these patients. Additionally, several Streptococcus strains demonstrated correlations between the respiratory and gut microbiota in CAP patients. By integrating host response data, we identified that Streptococcus oralis (SOR) was associated with host pathways involved in the innate immune response to infection. This microbe-host interaction was further validated in a newly enrolled cohort of 22 patients with influenza infection. The host-SOR interaction was also validated in a mouse model, where SOR showed protective efficacy against influenza virus infection comparable to the well-established respiratory probiotic Lactobacillus rhamnosus GG. Pre-aspiration of SOR in mice significantly mitigated body weight loss, reduced lung inflammation, and lowered viral loads following influenza challenge. SOR decreased the levels of pro-inflammatory cytokines such as TNF-α, IL-6, IL-10, IL-1β, GM-CSF, and IL-2 in bronchoalveolar lavage fluid (BALF) on day 7 post-infection. Host response profiling revealed that SOR priming activated a robust innate immune response during the early stage of infection, which resolved as the host began to recover. Additionally, metabolic profiling of BALF from SOR-treated mice revealed an increase in the abundance of metabolites such as 3-oxobutyryl-carnitine, Haloperidol and convolvulinin, suggesting that these metabolites may mediate the protective effects of SOR. Conclusions These findings suggest that respiratory commensals, such as Streptococcus oralis, play a crucial role in immune protection by inducing a timely innate immune response to prevent the progression of CAP. This abstract is funded by: National Key R&D Program of China