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
-
- 2,630
- views
-
- 392
- downloads
-
- 47
- 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 T6SS of Pseudomonas aeruginosa plays an essential role in the establishment of chronic infections. Inflammasome-mediated inflammatory cytokines are crucial for host defense against bacterial infections. We found that P. aeruginosa infection activates the non-canonical inflammasome in macrophages, yet it inhibits the downstream activation of the NLRP3 inflammasome. The VgrG2b of P. aeruginosa is recognized and cleaved by caspase-11, generating a free C-terminal fragment. The VgrG2b C-terminus can bind to NLRP3, inhibiting the activation of the NLRP3 inflammasome by rejecting NEK7 binding to NLRP3. Administration of a specific peptide that inhibits caspase-11 cleavage of VgrG2b significantly improves mouse survival during infection. Our discovery elucidates a mechanism by which P. aeruginosa inhibits host immune response, providing a new approach for the future clinical treatment of P. aeruginosa infections.
-
- Immunology and Inflammation
- Medicine
Preterm infants are susceptible to neonatal sepsis, a syndrome of pro-inflammatory activity, organ damage, and altered metabolism following infection. Given the unique metabolic challenges and poor glucose regulatory capacity of preterm infants, their glucose intake during infection may have a high impact on the degree of metabolism dysregulation and organ damage. Using a preterm pig model of neonatal sepsis, we previously showed that a drastic restriction in glucose supply during infection protects against sepsis via suppression of glycolysis-induced inflammation, but results in severe hypoglycemia. Now we explored clinically relevant options for reducing glucose intake to decrease sepsis risk, without causing hypoglycemia and further explore the involvement of the liver in these protective effects. We found that a reduced glucose regime during infection increased survival via reduced pro-inflammatory response, while maintaining normoglycemia. Mechanistically, this intervention enhanced hepatic oxidative phosphorylation and possibly gluconeogenesis, and dampened both circulating and hepatic inflammation. However, switching from a high to a reduced glucose supply after the debut of clinical symptoms did not prevent sepsis, suggesting metabolic conditions at the start of infection are key in driving the outcome. Finally, an early therapy with purified human inter-alpha inhibitor protein, a liver-derived anti-inflammatory protein, partially reversed the effects of low parenteral glucose provision, likely by inhibiting neutrophil functions that mediate pathogen clearance. Our findings suggest a clinically relevant regime of reduced glucose supply for infected preterm infants could prevent or delay the development of sepsis in vulnerable neonates.
