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Association of Diabetes Mellitus With a Shared Hyperinflammatory Immune Response in Patients With Melioidosis and
Patpong Rongkard1,2, Barbara Kronsteiner1,2, Clare Eckold3
1NDM Centre for Global Health Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
Background:
Melioidosis is a serious infection caused by the bacterium Burkholderia pseudomallei with a case fatality rate of up to 40% in Northeast Thailand. Diabetes mellitus (DM) increases the risk of developing melioidosis by 12-fold. A similar, but less marked relationship with DM is seen in patients with tuberculosis, with a 3-fold increased risk of developing tuberculosis in people with DM. However, the mechanisms underlying the impact of DM on infection are not fully understood.
Methods:
Eighty-one patients with acute melioidosis from Northeast Thailand and 151 patients with tuberculosis from South Africa, Indonesia, Romania, and Peru, along with uninfected control cohorts, were studied by whole-blood RNA sequencing. Both supervised and unsupervised data analysis approaches, were performed including differential gene expression, pathway, and weighted gene coexpression network analyses.
Results:
DM status was associated with a hyperinflammatory response to both melioidosis and tuberculosis, with increased neutrophil and platelet degranulation and exaggerated activation of coagulation and scavenger activation pathways, along with decreased phosphoinositide 3-kinase protein kinase B signaling. In melioidosis, changes with DM were subtle but also included increased tumor necrosis factor signaling via nuclear factor κB and enhancement of endoplasmic reticulum stress and unfolded protein responses. DM-related changes were more distinct in tuberculosis, with marked reduction of interferon signaling responses.
Conclusions:
DM is associated with enhanced nonspecific inflammatory responses in both melioidosis and tuberculosis and an impaired interferon-mediated response to tuberculosis, with implications for future host-directed therapies.
Insights
Diabetes mellitus (DM) exacerbates infections like melioidosis and tuberculosis by heightening inflammatory responses. This study reveals DM impairs crucial interferon signaling in tuberculosis, impacting treatment strategies.
Area of Science:
- Infectious Diseases
- Immunology
- Genomics
Background:
- Melioidosis, caused by *Burkholderia pseudomallei*, has a high fatality rate, especially in Thailand.
- Diabetes mellitus (DM) significantly increases susceptibility to melioidosis (12-fold) and tuberculosis (3-fold).
- The precise mechanisms linking DM to increased infection risk remain unclear.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the impact of DM on host immune responses during melioidosis and tuberculosis.
- To compare gene expression patterns in patients with DM and these infections against healthy controls.
Main Methods:
- Whole-blood RNA sequencing was performed on 81 melioidosis patients (Thailand) and 151 tuberculosis patients (various countries) with matched controls.
- Supervised and unsupervised analyses, including differential gene expression, pathway analysis, and weighted gene coexpression network analysis, were employed.
Main Results:
- DM status correlated with hyperinflammation in both melioidosis and tuberculosis, marked by increased neutrophil/platelet degranulation and coagulation pathway activation.
- DM led to decreased phosphoinositide 3-kinase/protein kinase B signaling in both infections.
- Specific to melioidosis, DM increased TNF signaling and ER stress; in tuberculosis, DM distinctly reduced interferon signaling.
Conclusions:
- DM enhances non-specific inflammatory responses in melioidosis and tuberculosis.
- DM impairs interferon-mediated immunity in tuberculosis, suggesting potential therapeutic targets.
- Findings have implications for developing host-directed therapies for infections in diabetic patients.
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