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PPE38-Secretion-Dependent Proteins of M. tuberculosis Alter NF-kB Signalling and Inflammatory Responses in

James Gallant1,2, Tiaan Heunis1,3, Caroline Beltran1

  • 1Department of Science and Technology/National Research Foundation Centre of Excellence in Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Frontiers in Immunology
|July 19, 2021
PubMed

Insights

Tuberculosis bacteria lacking the PPE38 protein show reduced virulence and dampen the host

Area of Science:

  • Microbiology
  • Immunology
  • Molecular Biology

Background:

  • The PPE-PGRS and PPE-MPTR protein secretion is crucial for Mycobacterium tuberculosis virulence.
  • A deletion in the ppe38-71 operon abolishes this secretion and is linked to increased virulence.
  • The specific role of PPE38-dependent proteins in modulating the host immune response remains unclear.

Purpose of the Study:

  • To identify proteins dependent on PPE38 for secretion.
  • To elucidate the role of these proteins in the innate immune response.
  • To understand the mechanism by which M. tuberculosis modulates macrophage responses.

Main Methods:

  • Temporal proteomics to identify secreted proteins.
  • Protein turnover analysis in a macrophage infection model.
  • Analysis of inflammatory pathways (RelB/p50 and canonical NF-kB) in infected macrophages.

Main Results:

  • Macrophages infected with PPE38-deficient M. tuberculosis showed a decreased pro-inflammatory response compared to wild-type.
  • The dampened inflammatory response was linked to the activation of the RelB/p50 pathway.
  • The canonical inflammatory pathway remained active during infection with wild-type M. tuberculosis.

Conclusions:

  • M. tuberculosis PPE/PPE proteins regulated by PPE38 modulate macrophage inflammatory responses.
  • This modulation occurs through the NF-kB signaling pathway, specifically involving RelB/p50.
  • PPE38 plays a key role in M. tuberculosis's ability to manipulate the host innate immunity.
Keywords:
Mycobacterium tuberculosisNF-KB signallingPE/PPEmacrophageproteomics

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