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Biology subjects

Kwa, A. L.-H.

Publications and source records attributed to Kwa, A. L.-H..

2 recordsLinked to original sources

Assessing bactericidal dynamics of persister-manifested clinical isolates in the presence of macrophages and antibiotics

Antibiotics are often depicted to reduce bacterial load for immuno-clearance. Recurring infections can be caused by bacteria persisters that survived antibiotic treatment. It is unclear how the host immunity manages infection by persister-manifested strains during antibiotic treatment. Differentiated THP-1 macrophages were exposed to persister-manifested clinical isolates at various multiplicities-of-infection (MOI), in the presence or absence of meropenem. Across all MOIs, meropenem did not greatly reduce the intracellular bacterial load nor eradicate all extra-macrophagic non-persister bacteria. Bactericidal effects on extracellular bacteria vary for each strain after meropenem treatment in mildly infected macrophages. In severely infected macrophages, extra-macrophagic bacteria of all isolates decreases in numbers followed by a bacteriostatic-like effect. Our findings contradict the common notion that antibiotics generally reduce the bacterial load for immune clearance. Our study suggests that the bactericidal effects of meropenem differs with host presence and can be dependent on bacterial load.

immunology↗

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↗