Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response

  1. Amelia E Hinman
  2. Charul Jani
  3. Stephanie C Pringle
  4. Wei R Zhang
  5. Neharika Jain
  6. Amanda J Martinot
  7. Amy K Barczak  Is a corresponding author
  1. Massachusetts General Hospital, United States
  2. 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.

The following data sets were generated

Article and author information

Author details

  1. Amelia E Hinman

    The Ragon Institute, Massachusetts General Hospital, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Charul Jani

    The Ragon Institute, Massachusetts General Hospital, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Stephanie C Pringle

    The Ragon Institute, Massachusetts General Hospital, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Wei R Zhang

    The Ragon Institute, Massachusetts General Hospital, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Neharika Jain

    Tufts University Cummings School of Veterinary Medicine, Grafton, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Amanda J Martinot

    Tufts University Cummings School of Veterinary Medicine, Grafton, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Amy K Barczak

    Medicine/Infectious Diseases, Massachusetts General Hospital, Cambridge, United States
    For correspondence
    ABARCZAK@mgh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3806-2381

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.

Reviewing Editor

  1. Christina L Stallings, Washington University School of Medicine, United States

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.

Version history

  1. Received: September 16, 2021
  2. Preprint posted: October 6, 2021 (view preprint)
  3. Accepted: October 29, 2021
  4. Accepted Manuscript published: November 10, 2021 (version 1)
  5. Version of Record published: November 23, 2021 (version 2)

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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  1. Amelia E Hinman
  2. Charul Jani
  3. Stephanie C Pringle
  4. Wei R Zhang
  5. Neharika Jain
  6. Amanda J Martinot
  7. Amy K Barczak
(2021)
Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response
eLife 10:e73984.
https://doi.org/10.7554/eLife.73984

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https://doi.org/10.7554/eLife.73984

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