The function of TLR2 and the microbiome in macrophage-dependent dissemination of nontuberculous mycobacterial gut infection.

Background: Nontuberculous mycobacteria (NTM) infections are increasing in incidence and mortality worldwide, yet the Results: In wild-type microbiome-colonized larvae, MAC 101 predominantly localizes in the posterior gut, in contrast to an anterior-biased distribution for Mma20 after 2.5 days of immersion infection. Both MAC 101 and Mma20 disseminate to posterior body region after 2.5 days of immersion infection. Robotic gut microinjection confirms the protective roles of TLR2 and the microbiome against proliferation of MAC 101 and Mma20. Expression analysis of downstream genes indicate that patterns of TLR2-dependent gene regulation differ between the two NTM species and show that the presence or absence of the microbiome differentially influences specific transcriptional responses to infection. Macrophage ablation studies show that macrophages facilitate dissemination of gut bacteria to the posterior body region. Quantification of macrophages containing bacteria throughout the body show that the dissemination of bacteria by macrophages depends on TLR2, but not on the microbiome. Using the same approach, TLR2 chemical antagonist treatment confirms the results observed in Conclusions: TLR2 and the microbiome play critical roles in modulating host responses to MAC 101 and Mma20 gut infection. Our findings provide new insights into the coordinated roles of TLR2 signaling and the microbiome in controlling infection of mycobacteria via the gut and underscore the importance of TLR2 in macrophage function during mycobacterial gut infection and dissemination.