Biology subjects

Sia, W. R.

Publications and source records attributed to Sia, W. R..

2 recordsLinked to original sources

bioRxiv2025

Restoration of MAIT cell function in healthcare-associated bacterial infections supports recovery of carbapenem efficacy against resistant bacteria

Antimicrobial resistance (AMR) presents a major clinical challenge to patients with healthcare-associated infections (HAIs), particularly among immunocompromised individuals and patients with comoribidites, who often exhibit an impaired mucosa-associated invariant T (MAIT) cell pool. MAIT cells are innate-like T cells enriched in mucosal tissues, possess potent antibacterial activity, and restoration of their function may offer a host-directed strategy against drug-resistant pathogens. We evaluated how stimulation with cognate antigen in combination with various cytokines, modulates MAIT cell cytotoxicity and enhances carbapenem activity. Under optimal conditions, MAIT cells exhibited increased expression of antimicrobial cytolytic proteins and efficiently killed cells pulsed with MAIT cell antigen. IL-15 or IL-2 plus IL-7 were particularly effective in promoting polyfunctional cytotoxic responses. Secretomes from cytokine-stimulated MAIT cells restored the activity of imipenem against engineered E. coli expressing the clinically relevant carbapenemases blaNDM-1, blaKPC-2, and blaOXA-48, strongly reducing bacterial growth, viability, and metabolic activity. Notably, IL-2 plus IL-7 stimulation enabled expansion and functional restoration of MAIT cells from HAI patients, whose baseline MAIT cell numbers and responses were diminished. These findings demonstrate that tailored stimulation can reinvigorate MAIT cell effector function and augment antibiotic efficacy, supporting a role for MAIT cells in adjunct immunotherapeutic strategy to combat AMR in vulnerable patient populations. Category of manuscript: Research Article.

immunology↗

bioRxiv2020

Human MAIT cell cytolytic effector proteins synergize to overcome carbapenem resistance in Escherichia coli

Mucosa-associated invariant T (MAIT) cells are abundant antimicrobial T cells in humans, and recognize antigens derived from the microbial riboflavin biosynthetic pathway presented by the MHC-Ib-related protein (MR1). However, the mechanisms responsible for MAIT cell antimicrobial activity are not fully understood, and the efficacy of these mechanisms against antibiotic resistant bacteria has not been explored. Here, we show that MAIT cells mediate MR1-restricted antimicrobial activity against E. coli clinical strains in a manner dependent on the activity of cytolytic proteins, but independent of production of pro-inflammatory cytokines or induction of apoptosis in infected cells. The combined action of the pore-forming antimicrobial protein granulysin and the serine protease granzyme B released in response to TCR-mediated recognition of MR1-presented antigen is essential to mediate control against both cell-associated and free-living E. coli. Furthermore, MAIT cell-mediated bacterial control extend to multidrug-resistant E. coli primary clinical isolates additionally resistant to carbapenems, a class of last resort antibiotics. Notably, high levels of granulysin and granzyme B in the MAIT cell secretomes directly damage bacterial cells by increasing their permeability, rendering initially resistant E. coli susceptible to the bactericidal activity of carbapenems. These findings define the role of cytolytic effector proteins in MAIT cell-mediated antimicrobial activity, and indicate that granulysin and granzyme B synergize to restore carbapenem bactericidal activity and overcome carbapenem resistance in E. coli. One Sentence SummaryPotent antimicrobial activity of human MAIT cells overcomes carbapenem-resistance in control of Escherichia coli

immunology↗