Ultra-small Saccharibacteria modulate immunoactivation through type IV pili and TLR2 2259816

Abstract

Abstract Introduction Saccharibacteria (TM7) are episymbiont, that grow on the surface of host bacteria such as Schaalia and Actinomyces (Actinobacteria). They are positively associated with inflammatory diseases within the human microbiome, yet their mechanisms for interacting with the human host and contributing to diseases remain unknown. This study investigated tripartite interactions between TM7, their host/non-host bacteria and their human host. Methods Numerous oral epithelial cell lines were infected with TM7 strains their host/non-host bacteria, and their co-culture, followed by analysis of pro-inflammatory cytokine responses and downstream interaction with epithelial cells. Results TM7 dampened innate immune responses induced by both their host and non-host Actinobacteria in oral epithelial cells. Follow up transcriptomic analysis revealed host bacteria activated TLR2 pathway, while TM7 inhibited it through close interaction between TM7 Type IV pili (T4P) and TLR2 receptor, leading to TLR2 clustering and endocytosis via caveolin, thereby inhibiting host and non-host Actinobacteria induced epithelial innate immune response. Endocytosed TM7 was processed to lysosome, however, a fraction of TM7 persisted and survived to reinfect its host-bacteria upon mechanical lysis. Conclusion This study highlights the role of TM7 in inflammatory diseases and offer novel mechanistic insights into how TM7 influence immune activation and inflammation, highlighting their potential role in shaping the microbiome and contributing to inflammatory disease dynamics. Funding Source National Institute of Dental and Craniofacial Research (NIDCR) under awards 1R01DE031274 (B.B.) and 1R01DE023810 (X.H., J.S.M.). Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)