Enrichment of Streptococcus oralis in respiratory microbiome enhance innate immunity and protects against influenza infection

Respiratory microbial dysbiosis has been implicated in the occurrence and progression of community-acquired pneumonia (CAP). However, the dynamic variation in the respiratory microbiota and its interaction with the host response remain poorly understood. Here, we performed metagenomic analysis of respiratory and gut microbiota, along with blood transcriptomics, using longitudinally collected samples from 38 CAP patients. CAP patients presented disrupted sputum microbiota at the early, middle, and late stages of hospitalization. Microbial pathways involved in peptidoglycan biosynthesis and immune evasion, particularly contributed by the Streptococcus genus, were enriched in CAP patients. Additionally, several Streptococcus strains demonstrated correlation between respiratory and gut microbiota in CAP patients. By incorporating host response data, we revealed that Streptococcus oralis (SOR) was associated with host pathways involved in the innate immune response to infection, and this microbe‒host interaction was reproduced in a newly enrolled CAP cohort consisting of 22 patients with influenza infection. The host-SOR interaction was validated in a mouse model, where SOR demonstrated protective efficacy against influenza virus infection comparable to that of the well-established respiratory probiotic Lactobacillus rhamnosus GG. Preaspiration of SOR in mice significantly mitigated body weight loss, reduced lung inflammation, and lowered viral loads following influenza virus challenge. Host response profiling indicated that SOR priming activated a greater innate immune response at the early stage of infection and that this response resolved timely as the host began to recover. These findings suggest that respiratory commensals play an immune-protective role by inducing a timely innate immune response to prevent CAP progression.