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

• Published in: PLoS biology Vol. 18; no. 6; p. e3000644
• Main Authors: Boulouis, Caroline, Sia, Wan Rong, Gulam, Muhammad Yaaseen, Teo, Jocelyn Qi Min, Png, Yi Tian, Phan, Thanh Kha, Mak, Jeffrey Y W, Fairlie, David P, Poon, Ivan K H, Koh, Tse Hsien, Bergman, Peter, Lim, Chwee Ming, Wang, Lin-Fa, Kwa, Andrea Lay Hoon, Sandberg, Johan K, Leeansyah, Edwin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.06.2020; Public Library of Science (PLoS)
• Subjects: Analysis; Anti-Infective Agents - pharmacology; Antibiotic resistance; Antibiotics; Antigens; Antigens, Differentiation, T-Lymphocyte - metabolism; Antiinfectives and antibacterials; Antimicrobial activity; Antimicrobial agents; Apoptosis; Bacteria; Bacterial infections; Bacterial Load - drug effects; Bactericidal activity; Biology; Biology and Life Sciences; Carbapenems; Carbapenems - pharmacology; Clinical isolates; Cytokines; Cytotoxicity, Immunologic - drug effects; Dosage and administration; Drug resistance; Drug resistance in microorganisms; Drug Resistance, Bacterial - drug effects; E coli; Escherichia coli; Escherichia coli - drug effects; Flow cytometry; Funding; Granzyme B; Granzymes - metabolism; HeLa Cells; Hospitals; Humans; Infections; Infectious diseases; Inflammation; Kinetics; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medical schools; Medicin och hälsovetenskap; Medicine; Medicine and Health Sciences; Microorganisms; Mucosa; Mucosal-Associated Invariant T Cells - immunology; Multidrug resistance; Otolaryngology; Pathogens; Permeability; Pharmacy; Pore formation; Proteins; R&D; Research & development; Research and analysis methods; Riboflavin; Serine; Serine proteinase; Surgery; Synergism; T cell receptors; T cells; T-cell receptor; Vitamin B; Sweden; Singapore; Queensland Australia; Australia
• DOI: 10.1371/journal.pbio.3000644
• ISSN: 1545-7885; 1544-9173

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 Escherichia 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 T cell receptor (TCR)-mediated recognition of MR1-presented antigen is essential to mediate control against both cell-associated and free-living, extracellular forms of E. coli. Furthermore, MAIT cell-mediated bacterial control extends 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.