Poster Presentation CD1-MR1 2024

Herpes simplex viruses incapacitate host cell presentation of metabolites by MR1 (#111)

Carolyn Samer 1 2 , Madeline Cranney 1 2 , Hamish EG McWilliam 3 , Brian P McSharry 1 4 , James G Burchfield 2 5 , Richard J Stanton 6 , Jamie Rossjohn 6 7 , Jose A Villadangos 3 7 , Allison Abendroth 1 2 , Barry Slobedman 1 2
  1. Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
  2. Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
  3. Department of Microbiology and Immunology, The Peter Doherty Institute of Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
  4. School of Dentistry and Medical Sciences, Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia
  5. School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia
  6. Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, Wales
  7. Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, University of Melbourne, Melbourne, VIC, Australia

Herpes simplex viruses (HSV) infect orofacial and genital mucosa, relying on expression of immunomodulatory viral proteins to evade detection and eradication by resident immune populations. Currently the role of Mucosal-associated invariant T (MAIT) cells during HSV infections, and the impact of viral lesions on the availability of Major Histocompatibility Complex, Class-I-related (MR1) ligands, remain unknown. Nevertheless, our in vitro experiments confirm increased retention of mature MR1 on the plasma membrane of HSV infected cells, which is rapidly and profoundly countered by a multi-pronged, virus-driven inhibition of MR1 protein synthesis and ligand-mediated trafficking. Using techniques including flow cytometry, RT-qPCR, immunoblotting, and high throughput quantitative fluorescence microscopy, we identify downregulation of MR1 transcripts, proteasomal degradation of immature MR1 from the endoplasmic reticulum, and accumulation of mature forms in early endosomal compartments, in HSV infected cells. We identify three viral gene products, namely virion host shutoff (vhs), infected cell protein (ICP)22 and unique short (US)3 protein, that contribute in different ways to this immunomodulatory downregulation of MR1. Some of these viral modulatory mechanisms do not impact classical antigen presentation molecules, reflecting a specific biological imperative to minimise surface MR1. This inhibition of MR1 by HSV potentially protects infected cells from early TCR-mediated effector functions such as MAIT cell cytolytic killing of virally infected cells or those during co-infection with microbial pathogens that express metabolites presented via MR1, and the synergistic proinflammatory effects from combined TCR independent and dependent activation.