Inflammasome regulation by the cell surface ecto-5′-nucleotidase of the oral commensal, Streptococcus oralis

Streptococcus oralis is a commensal oral bacterium that acts as an opportunistic pathogen, causing systemic diseases, such as infective endocarditis and aspiration pneumonia. However, the specific molecular mechanisms underlying its transition from commensal to pathogenic state remain unclear. In this study, to further elucidate the mechanisms underlying virulence expression, we identified and characterized the cell surface-associated ecto-5'-nucleotidase (Nt5e) in S. oralis. Biochemical analysis revealed Nt5e as a metal-dependent enzyme dephosphorylating ATP and producing adenosine, an immunosuppressive molecule that inhibits macrophage activation. Additionally, Nt5e was a critical regulator of innate immunity, particularly inflammasome activation, via environmental ATP metabolism. Analysis of an isogenic nt5e deletion mutant and its complemented strain revealed that cell surface-associated Nt5e played a crucial role in degrading extracellular ATP. The Nt5e-orchestrated mechanism possibly maintained the host-bacteria homeostasis under normal conditions, whereas its dysregulation facilitated pathogenicity in specific circumstances. Our study provides new insights into the mechanisms by which oral commensals modulate host immune responses and highlights Nt5e as a potential therapeutic target for S. oralis-associated systemic diseases.