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Published on: January 7, 2019
Mucosal-associated invariant T (MAIT) cells are reduced and dysfunctional in acute melioidosis
Fazle Rabbi Chowdhury1,2,3,4, Martha Zewdie1,2, Priyanka Abraham1,2,4
1Peter Medawar Building for Pathogen Research, University of Oxford, 3 South Parks Road, Oxford, OX1 3SY, UK.
Abstract:
Burkholderia pseudomallei (BP), the causative agent of melioidosis, is a major cause of sepsis in Southeast Asia, especially in people with diabetes mellitus (DM). The role of Mucosal-associated invariant T (MAIT) cells; innate-like T cells important for antibacterial immunity; in melioidosis is unknown. We measured MAIT cell activation by BP in vitro using co-culture assays with THP-1 cells, and evaluated MAIT cell frequency, activation, and function ex vivo in an observational cohort (n = 120) of melioidosis patients and endemic controls with and without DM in Thailand. We show that BP induces IFN-γ secretion by MAIT cells in a cytokine dependent manner. In acute melioidosis, circulating MAIT cells, particularly the double-negative (DN) subset, were significantly reduced, and highly activated but dysfunctional, with reduced IFN-γ responses to BP and E. coli which were restored upon recovery. Among acute patients, non-survivors showed lower granzyme B and IFN-γ expression. Acute melioidosis patients with DM co-morbidity exhibited reduced DN MAIT cell frequency and responses to E. coli compared to non-DM patients. Overall, the frequency and function of MAIT cells is impaired during acute melioidosis, especially in patients with DM, indicating a key role for these cells in antibacterial defence and disease susceptibility.
Insights
Mucosal-associated invariant T (MAIT) cells are reduced and dysfunctional in melioidosis patients, particularly those with diabetes. Impaired MAIT cell function contributes to disease severity and susceptibility.
Area of Science:
- Immunology
- Infectious Diseases
- Microbiology
Background:
- Melioidosis, caused by Burkholderia pseudomallei (BP), is a significant cause of sepsis in Southeast Asia, particularly affecting individuals with diabetes mellitus (DM).
- The role of Mucosal-associated invariant T (MAIT) cells, crucial for innate antibacterial immunity, in melioidosis pathogenesis remains unclear.
Purpose of the Study:
- To investigate the activation, frequency, and function of MAIT cells in patients with melioidosis.
- To assess the impact of diabetes mellitus on MAIT cell responses during melioidosis.
Main Methods:
- In vitro co-culture assays to measure MAIT cell activation by BP.
- Ex vivo analysis of MAIT cell frequency, activation, and function in a cohort of melioidosis patients and endemic controls in Thailand.
- Comparison of MAIT cell responses between patients with and without diabetes mellitus.
Main Results:
- Burkholderia pseudomallei induced IFN-γ secretion by MAIT cells in a cytokine-dependent manner.
- Acute melioidosis patients exhibited reduced frequencies of circulating MAIT cells, especially the double-negative (DN) subset, which were hyperactivated but dysfunctional.
- MAIT cells from acute patients showed impaired IFN-γ responses to BP and E. coli, with reduced granzyme B and IFN-γ expression in non-survivors.
- Patients with diabetes and melioidosis had lower DN MAIT cell frequencies and impaired responses to E. coli compared to non-diabetic patients.
Conclusions:
- MAIT cell frequency and function are significantly impaired during acute melioidosis.
- Impaired MAIT cell responses, particularly in the double-negative subset, are associated with increased disease severity and susceptibility, especially in patients with diabetes mellitus.
- MAIT cells play a critical role in antibacterial defense against melioidosis.
