PUBLICATION
The function of TLR2 and the microbiome in macrophage-dependent dissemination of nontuberculous mycobacterial gut infection
- Authors
- Liu, L., Hu, W., Spaink, H.P.
- ID
- ZDB-PUB-260530-20
- Date
- 2026
- Source
- International journal of biological sciences 22: 535953845359-5384 (Journal)
- Registered Authors
- Keywords
- Nontuberculous mycobacteria, TLR2, microbiome, natural immersion infection, zebrafish
- MeSH Terms
- none
- PubMed
- 42212334 Full text @ Int. J. Biol. Sci.
Citation
Liu, L., Hu, W., Spaink, H.P. (2026) The function of TLR2 and the microbiome in macrophage-dependent dissemination of nontuberculous mycobacterial gut infection. International journal of biological sciences. 22:535953845359-5384.
Abstract
Background Nontuberculous mycobacteria (NTM) infections are increasing in incidence and mortality worldwide, yet the in vivo determinants of early intestinal colonization and subsequent dissemination remain poorly defined. Using a zebrafish larval model, we studied dissemination of two NTM strains, Mycobacterium avium subspecies hominissuis Chester (strain MAC 101) and M. marinum (strain Mma20) through the gastrointestinal (GI) tract. We performed bacterial immersion experiments and gut microinjection with these pathogens using tlr2 mutant and wild-type zebrafish larvae in both germ-free (GF) and microbiome-colonized conditions. This study for the first time shows the roles of Toll-like receptor 2 (TLR2) and the microbiome in orchestrating immune responses in NTM gut infection and dissemination.
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 tlr2 mutant larvae. Live imaging of macrophage trajectories after bacterial gut microinjection show that macrophage motility after infection is impaired in tlr2 mutant larvae compared to the wild type. Notably, the effect of TLR2 on macrophage motility differs between GF and microbiome-colonized conditions.
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.
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