Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response
- Massachusetts General Hospital, United States
- Tufts University Cummings School of Veterinary Medicine, United States
Abstract
For many intracellular pathogens, the phagosome is the site of events and interactions that shape infection outcome. Phagosomal membrane damage, in particular, is proposed to benefit invading pathogens. To define the innate immune consequences of this damage, we profiled macrophage transcriptional responses to wild-type Mycobacterium tuberculosis (Mtb) and mutants that fail to damage the phagosomal membrane. We identified a set of genes with enhanced expression in response to the mutants. These genes represented a late component of the TLR2-dependent transcriptional response to Mtb, distinct from an earlier component that included Tnf. Expression of the later component was inherent to TLR2 activation, dependent upon endosomal uptake, and enhanced by phagosome acidification. Canonical Mtb virulence factors that contribute to phagosomal membrane damage blunted phagosome acidification and undermined the endosome-specific response. Profiling cell survival and bacterial growth in macrophages demonstrated that the attenuation of these mutants is partially dependent upon TLR2. Further, TLR2 contributed to the attenuated phenotype of one of these mutants in a murine model of infection. These results demonstrate two distinct components of the TLR2 response and identify a component dependent upon endosomal uptake as a point where pathogenic bacteria interfere with the generation of effective inflammation. This interference promotes TB pathogenesis in both macrophage and murine infection models.
Data availability
RNAseq data is accessible on the NCBI GEO website GSE144330.
Article and author information
Author details
Funding
MGH Transformative Scholar Award
- Amy K Barczak
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in accordance with guidelines of the Massachusetts General Hospital Institutional Care and Use Committee, under the approved protocols 2014N000297 and 2014N000311.
Copyright
© 2021, Hinman et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response
eLife 10:e73984.
https://doi.org/10.7554/eLife.73984
