A moonlighting protein secreted by a nasal microbiome fortifies the innate host defense against bacterial and viral infections

Background: Evidence suggests that the human respiratory tract, as with the gastrointestinal tract, has evolved to its current state in association with commensal microbes. However, little is known as how the airway microbiome affected airway immune development. Here, we uncover a previously unidentified mode of interaction between host airway immunity and a unique strain of Staphylococcus epidermidis, a predominant species of the nasal microbiome. Results: Intranasal inoculation of S. epidermidis AIT01 accompanied the active recruitment of neutrophils and monocytes into mouse lungs on the murine model. The recruitment of the immune cells resulted in the complete protection of the murine host against Pseudomonas aeruginosa respiratory infection. Interestingly, an AIT01-secreted protein identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a well-known bacterial moonlighting protein, mediated this protective effect. Intranasal delivery of the purified protein conferred significant resistance against other additional airway infections of Gram-negative pathogens or influenza A virus. Moreover, single cell RNA-seq analysis using mouse lung cells revealed that transcription of genes involved in cytokine production, phagocytosis, chemotaxis, and immune cell migration was considerably upregulated in neutrophils and monocytes in response to the treatment with the protein. Conclusions: Our results illustrate how an indigenous nasal microbe and its secretory protein can extensively instigate an innate immune defense. We also suggest a promising prophylactic option for airway infections in the era of global pandemics. Keywords: Staphylococcus epidermidis, human nasal microbiome, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), innate immune defense