Investigating Non-sterilizing Cure in TB Patients at the End of Successful Anti-TB Therapy

Caroline G.G. Beltran*, Tiaan Heunis, James Gallant, Rouxjeane Venter, Nelita du Plessis, Andre G. Loxton, Matthias Trost, Jill Winter, Stephanus T. Malherbe, Bavesh D. Kana, Gerhard Walzl

*Corresponding author for this work

    Research output: Contribution to JournalArticleAcademicpeer-review

    Abstract

    Mycobacterium tuberculosis (Mtb) is extremely recalcitrant to antimicrobial chemotherapy requiring 6 months to treat drug-sensitive tuberculosis (TB). Despite this, 4–10% of cured patients will develop recurrent disease within 12 months after completing therapy. Reasons for relapse in cured TB patients remains speculative, attributed to both pathogen and host factors. Populations of dormant bacilli are hypothesized to cause relapse in initially cured TB patients however, development of tests to convincingly demonstrate their presence at the end of anti-TB treatment has been challenging. Previous studies have indicated the utility of culture filtrate supplemented media (CFSM) to detect differentially culturable tubercle bacilli (DCTB). Here, we show that 3/22 of clinically cured patients retained DCTB in induced sputum and bronchoalveolar lavage fluid (BALF), with one DCTB positive patient relapsing within the first year of completing therapy. We also show a correlation of DCTB status with “unresolved” end of treatment FDG PET-CT imaging. Additionally, 19 end of treatment induced sputum samples from patients not undergoing bronchoscopy were assessed for DCTB, identifying a further relapse case with DCTB. We further show that induced sputum is a less reliable source for the DCTB assay at the end of treatment, limiting the utility of this assay in a clinical setting. We next investigated the host proteome at the site of disease (BALF) using multiplexed proteomic analysis and compared these to active TB cases to identify host-specific factors indicative of cure. Distinct signatures stratified active from cured TB patients into distinct groups, with a DCTB positive, subsequently relapsing, end of treatment patient showing a proteomic signature closer to active TB disease than cure. This exploratory study offers evidence of live Mtb, undetectable with conventional culture methods, at the end of clinically successful treatment and putative host protein biomarkers of active disease and cure. These findings have implications for the assessment of true sterilizing cure in TB patients and opens new avenues for targeted approaches to monitor treatment response.

    Original languageEnglish
    Article number443
    Pages (from-to)1-14
    Number of pages14
    JournalFrontiers in Cellular and Infection Microbiology
    Volume10
    DOIs
    Publication statusPublished - 25 Aug 2020

    Funding

    We are grateful to the study participants and to the South African MRC and the Catalysis Foundation for Health for funding this work. Funding. The financial assistance of the National Research Foundation (NRF) toward this research is hereby acknowledged. Opinions expressed and conclusions arrived at, are those of the author(s) and are not necessarily to be attributed to the NRF. Research reported in this publication was supported by the South African Medical Research Council. The content is solely the responsibility of the authors and does not necessarily represent the official views of the South African Medical Research Council. Funding was provided by the Catalysis Foundation for Health through the BMGF (OPP51919). GW leads the South African Research Chair Initiative (SARChI) in TB Biomarkers (#86535). RV acknowledges funding from the National Research Foundation (NRF), South African Medical Council (SAMRC), and Stellenbosch University.

    FundersFunder number
    Catalysis Foundation for Health
    National Research Foundation
    South African MRC
    Bill and Melinda Gates FoundationOPP51919, 86535
    Bill and Melinda Gates Foundation
    South African Medical Research Council
    Universiteit Stellenbosch

      Keywords

      • 18F-FDG PET-CT
      • BALF proteome analysis
      • differentially culturable tubercle bacteria
      • dormant
      • Mycobacterium tuberculosis
      • sterilizing cure
      • treatment response
      • tuberculosis

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