Persistent inflammation during anti-tuberculosis treatment with diabetes comorbidity
- National Institutes of Health, India
- Fundação José Silveira, Brazil
- Prof M Viswanathan Diabetes Research Center, India
- University of Massachusetts Medical School, United States
- National Institute for Research in Tuberculosis, India
Abstract
Diabetes mellitus (DM) increases risk for pulmonary tuberculosis (TB) and adverse treatment outcomes. Systemic hyper-inflammation is characteristic in people with TB and concurrent DM (TBDM) at baseline, but the impact of TB treatment on this pattern has not been determined. We measured 17 plasma cytokines and growth factors in longitudinal cohorts of Indian and Brazilian pulmonary TB patients with or without DM. Principal component analysis revealed virtually complete separation of TBDM from TB individuals in both cohorts at baseline, with hyper-inflammation in TBDM that continued through treatment completion at six months. By one year after treatment completion, there was substantial convergence of mediator levels between groups within the India cohort. Non-resolving systemic inflammation in TBDM comorbidity could reflect delayed lesion sterilization or non-resolving sterile inflammation. Either mechanism portends unfavorable long-term outcomes including risk for recurrent TB and for damaging immune pathology.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1 through 5.
Article and author information
Author details
Funding
CRDF Global (USB1-31149-XX-13)
- Hardy Kornfeld
CRDF Global (USB1-31149-XX-13)
- Vijay Viswanathan
National Institutes of Health (U01AI115940)
- Bruno B Andrade
Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Kiyoshi F Fukutani
Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Thabata Alves
Fundação de Amparo à Pesquisa do Estado da Bahia
- Paulo S Silveira-Mattos
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Kiyoshi F Fukutani
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Bruno B Andrade
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: All research presented here was conducted according to the principles expressed in the Declaration of Helsinki. The Indian cohort study was approved by the Ethics Committee of the Prof. M. Viswanathan Diabetes Research Centre (ECR/51/INST/TN/2013/MVDRC/01). The Brazilian cohort study was approved by the Ethics Committee of the Maternidade Climério de Oliveira, Federal University of Bahia (CAAE: 0115.0.054.000-09). Written informed consent was obtained from all participants at both sites.
Copyright
© 2019, Kumar 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.
Metrics
-
- 2,657
- views
-
- 394
- downloads
-
- 48
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Persistent inflammation during anti-tuberculosis treatment with diabetes comorbidity
eLife 8:e46477.
https://doi.org/10.7554/eLife.46477
Further reading
-
- Immunology and Inflammation
Macrophages control intracellular pathogens like Salmonella by using two caspase enzymes at different times during infection.
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets—a phenotype associated with dormancy—that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.
