Oral streptococci S. anginosus and S. mitis induce distinct morphological, inflammatory, and metabolic signatures in macrophages.

Oral streptococci, key players in oral biofilm formation, are implicated in oral dysbiosis and various clinical conditions, including dental caries, gingivitis, periodontal disease, and oral cancer. Specifically, Streptococcus anginosus is associated with esophageal, gastric, and pharyngeal cancers, while Streptococcus mitis is linked to oral cancer. However, no study has investigated the mechanistic links between these Streptococcus species and cancer-related inflammatory responses. As an initial step, we probed the innate immune response triggered by S. anginosus and S. mitis in RAW264.7 macrophages. These bacteria exerted time- and dose-dependent effects on macrophage morphology without affecting cell viability. Compared with untreated macrophages, macrophages infected with S. anginosus exhibited a robust proinflammatory response characterized by significantly increased levels of inflammatory cytokines and mediators, including TNF, IL-6, IL-1ß, NOS2, and COX2, accompanied by enhanced NF-κB activation. In contrast, S. mitis-infected macrophages failed to elicit a robust inflammatory response. Seahorse Xfe96 analysis revealed an increased extracellular acidification rate in macrophages infected with S. anginosus compared with S. mitis. At the 24-h time point, the presence of S. anginosus led to reduced extracellular itaconate, while S. mitis triggered increased itaconate levels, highlighting distinct metabolic profiles in macrophages during infection in contrast to aconitate decarboxylase expression observed at the 6-h time point. This initial investigation highlights how S. anginosus and S. mitis, two Gram-positive bacteria from the same genus, can prompt distinct immune responses and metabolic shifts in macrophages during infection.IMPORTANCEThe surge in head and neck cancer cases among individuals devoid of typical risk factors such as Human Papilloma Virus (HPV) infection and tobacco and alcohol use sparks an argumentative discussion around the emerging role of oral microbiota as a novel risk factor in oral squamous cell carcinoma (OSCC). While substantial research has dissected the gut microbiome's influence on physiology, the oral microbiome, notably oral streptococci, has been underappreciated during mucosal immunopathogenesis. Streptococcus anginosus, a viridans streptococci group, has been linked to abscess formation and an elevated presence in esophageal cancer and OSCC. The current study aims to probe the innate immune response to S. anginosus compared with the early colonizer Streptococcus mitis as an important first step toward understanding the impact of distinct oral Streptococcus species on the host immune response, which is an understudied determinant of OSCC development and progression.

Insights into the enigma of oral streptococci in carcinogenesis.

SUMMARYThe genus Streptococcus consists of a taxonomically diverse group of Gram-positive bacteria that have earned significant scientific interest due to their physiological and pathogenic characteristics. Within the genus Streptococcus, viridans group streptococci (VGS) play a significant role in the oral ecosystem, constituting approximately 80% of the oral biofilm. Their primary role as pioneering colonizers in the oral cavity with multifaceted interactions like adherence, metabolic signaling, and quorum sensing contributes significantly to the complex dynamics of the oral biofilm, thus shaping oral health and disease outcomes. Perturbations in oral streptococci composition drive oral dysbiosis and therefore impact host-pathogen interactions, resulting in oral inflammation and representing VGS as an opportunistic pathogen. The association of oral streptococci in tumors across distant organs, spanning the esophagus, stomach, pancreas, and colon, illuminates a potential association between oral streptococci, inflammation, and tumorigenesis. This finding emphasizes the need for further investigations into the role of oral streptococci in mucosal homeostasis and their involvement in carcinogenesis. Hence, here, we review the significance of oral streptococci in biofilm dynamics and how the perturbation may impact mucosal immunopathogenesis in the context of cancer, with a vision of exploiting oral streptococci for cancer intervention and for the development of non-invasive cancer diagnosis.