Mycobacterium tuberculosis curli pili (MTP) is associated with significant host metabolic pathways in an A549 epithelial cell infection model and contributes to the pathogenicity of Mycobacterium tuberculosis

Abstract

Introduction

A clear understanding of the metabolome of Mycobacterium tuberculosis and its target host cell during infection is fundamental for the development of novel diagnostic tools, effective drugs and vaccines required to combat tuberculosis. The surface-located Mycobacterium tuberculosis curli pili (MTP) adhesin forms initial contact with the host cell and is therefore important for the establishment of infection.

Objective

The aim of this investigation was to determine the role of MTP in modulating pathogen and host metabolic pathways in A549 epithelial cells infected with MTP proficient and deficient strains of M. tuberculosis.

Methods

Uninfected A549 epithelial cells, and those infected with M. tuberculosis V9124 wild-type strain, Δmtp and the mtp-complemented strains, were subjected to metabolite extraction, two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC-TOFMS) and bioinformatic analyses. Univariate and multivariate statistical tests were used to identify metabolites that were significantly differentially produced in the WT-infected and ∆mtp-infected A549 epithelial cell models, comparatively.

Results

A total of 46 metabolites occurred in significantly lower relative concentrations in the Δmtp-infected cells, indicating a reduction in nucleic acid synthesis, amino acid metabolism, glutathione metabolism, oxidative stress, lipid metabolism and peptidoglycan, compared to those cells infected with the WT strain.

Conclusion

The absence of MTP was associated with significant changes to the host metabolome, suggesting that this adhesin is an important contributor to the pathogenicity of M. tuberculosis, and supports previous findings of its potential as a suitable drug, vaccine and diagnostic target.

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Data availability

The datasets generated and/or analysed during the current study are not publicly available due to collaborative purposes and future publications but are available from the corresponding author on reasonable request. KEGG database reported in this study is accessible via [https://www.genome.jp/kegg/].

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Funding

This study was funded by MP’s South African National Research Foundation CPRR Grant 105841 Grantholder-linked bursary and project running costs, and a University of KwaZulu-Natal College of Health Sciences scholarship.

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Contributions

MP conceptualised and funded the study, MP, BP and DTL designed the study. KSR conducted experiments, analysed and interpreted the data and drafted the manuscript. DB processed the samples and performed GCxGC-TOFMS. MVR conducted statistical bioinformatic analyses. All authors contributed to and approved the manuscript.

Corresponding author

Correspondence to M. Pillay.

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KSR declares that she has no conflict of interest. DLT declares he has no conflict of interest. DB declares she has no conflict of interest. MVR declares she has no conflict of interest. BP declares he has no conflict of interest. MP declares she has no conflict of interest.

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Reedoy, K.S., Loots, D.T., Beukes, D. et al. Mycobacterium tuberculosis curli pili (MTP) is associated with significant host metabolic pathways in an A549 epithelial cell infection model and contributes to the pathogenicity of Mycobacterium tuberculosis. Metabolomics 16, 116 (2020). https://doi.org/10.1007/s11306-020-01736-5

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Keywords

  • M. tuberculosis curli pili
  • A549 epithelial cells
  • mtp
  • Adhesin
  • GCxGC-TOFMS
  • Metabolomics