Diabetes mellitus is associated with a shared hyper-inflammatory immune response in melioidosis and tuberculosis patients: an observational case-control study

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 increases the risk of developing melioidosis by 12-fold. A similar, but less marked, relationship with diabetes is seen in tuberculosis (TB) patients, with a 3-fold increased risk of developing TB in people with diabetes. However, the mechanisms underlying increased susceptibility are not fully understood.

81 acute melioidosis patients from Northeast Thailand and 151 TB patients from South Africa, Indonesia, Romania and Peru alongside uninfected control cohorts were studied by whole blood RNA sequencing. Both supervised and unsupervised data analysis approaches were performed including differential gene expression (DGE) analysis, pathway analyses, and weighted gene co-expression network analysis (WGCNA).

Diabetes status was associated with a hyper-inflammatory response to both melioidosis and TB, with increased neutrophil and platelet degranulation, and exaggerated activation of coagulation and scavenger activation pathways, alongside decreased phosphoinositide-3-kinase protein kinase B (P13K-Akt) signalling. In melioidosis, changes with diabetes were subtle but also included increased tumour necrosis factor (TNF) signalling via nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and enhancement of endoplasmic reticulum stress and unfolded protein responses. Diabetes-related changes were more distinct in TB, with marked reduction of interferon signalling responses.

Diabetes is associated with enhanced non-specific inflammatory responses in both melioidosis and TB and an impaired interferon-mediated response to TB, with implications for future host-directed therapies. Summary Diabetes status is associated with a hyper-inflammatory response to both melioidosis and TB, with increased neutrophil and platelet degranulation, and exaggerated activation of coagulation and scavenger activation pathways. The impact is more subtle in melioidosis but pronounced in tuberculosis with stunted interferon responses. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded by a Wellcome Trust Intermediate Clinical Fellowship (award ref WT100174/Z/12/Z). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics committees of the Faculty of Tropical Medicine, Mahidol University (TMEC 12-014); Sunpasitthiprasong Hospital, Ubon Ratchathani (017/2559) and the Oxford Tropical Research Ethics Committee (OXTREC35-15) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors