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
-
- 2,665
- views
-
- 395
- downloads
-
- 50
- 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
The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah-/- mice accumulated more hepatic lipid than did Aoah+/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah-/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah-/- mice also increased hepatic expression of Cd36 and Fabp3, which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara. Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.
-
- Cell Biology
- Immunology and Inflammation
Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.
