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Human MAIT cell cytolytic effector proteins synergize to overcome carbapenem resistance in Escherichia coli
journal contributionposted on 06.01.2021, 01:23 by Caroline Boulouis, Wan Rong Sia, Muhammad Yaaseen Gulam, Jocelyn Qi Min Teo, Thanh Phan, Jeffrey YW Mak, David P Fairlie, Ivan Poon, Tse Hsien Koh, Peter Bergman, Lin-Fa Wang, Andrea Lay Hoon Kwa, Johan K Sandberg, Edwin Leeansyah
Copyright: © 2020 Boulouis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
This research was supported by Swedish Research Council Grant 2015-00174, Marie Sklodowska Curie Actions, Cofund, Project INCA 600398, the Jonas Soderquist Foundation for Virology and Immunology, and the Petrus and Augusta Hedlund Foundation (EL). Further support came from the Swedish Research Council Grant 2016-03052, Swedish Cancer Society Grant CAN 2017/777, Center for Innovative Medicine Grant 20190732, and the National Institutes of Health Grant R01DK108350 (to JKS), as well as the CoSTAR-HS ARG Seed Fund 2018/02, NMRC Collaborative centre grant NMRC/CG/C005B/2017_SGH (to ALHK). CB is supported by the Karolinska Institutet Doctoral Grant and the Erik and Edith Fernstrom Foundation for Medical Research. PB is supported by a grant from the Swedish Research Council, the Stockholm County Council, Scandinavian Society for Antimicrobial Chemotherapy, The Swedish Foundation for Antimicrobial Resistance and the Karolinska Institutet. DPF acknowledges an ARC grant (CE140100011) and an NHMRC SPR Fellowship (1117017). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PublisherPublic Library of Science
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Science & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyBiologyLife Sciences & Biomedicine - Other TopicsINVARIANT T-CELLSCYTOKINE PRODUCTIONIMMUNE-RESPONSETISSUE-REPAIRACTIVATIONGRANULYSINBACTERIAENTEROBACTERIACEAEDELIVERYPROMOTEHela CellsHumansEscherichia coliCarbapenemsAntigens, Differentiation, T-LymphocyteAnti-Infective AgentsDrug Resistance, BacterialCytotoxicity, ImmunologicKineticsGranzymesBacterial LoadMucosal-Associated Invariant T CellsHeLa CellsDevelopmental Biology