Multi-targeted loss of the antigen presentation molecule MR1 during HSV-1 and HSV-2 infection

Carolyn Samer; Hamish E G McWilliam; Brian P McSharry; Thilaga Velusamy; James G Burchfield; Richard J Stanton; David C Tscharke; Jamie Rossjohn; Jose A Villadangos; Allison Abendroth; Barry Slobedman

doi:10.1016/j.isci.2024.108801

Multi-targeted loss of the antigen presentation molecule MR1 during HSV-1 and HSV-2 infection

iScience. 2024 Jan 4;27(2):108801. doi: 10.1016/j.isci.2024.108801. eCollection 2024 Feb 16.

Authors

Carolyn Samer¹, Hamish E G McWilliam^{2

3}, Brian P McSharry^{1

4}, Thilaga Velusamy⁵, James G Burchfield^{6

7}, Richard J Stanton⁸, David C Tscharke⁵, Jamie Rossjohn^{8

9}, Jose A Villadangos^{2

3}, Allison Abendroth¹, Barry Slobedman¹

Affiliations

¹ Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, and the Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia.
² Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia.
³ Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia.
⁴ School of Dentistry and Medical Sciences, Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia.
⁵ John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
⁶ Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
⁷ School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia.
⁸ Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, Wales.
⁹ Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

Abstract

The major histocompatibility complex (MHC), Class-I-related (MR1) molecule presents microbiome-synthesized metabolites to Mucosal-associated invariant T (MAIT) cells, present at sites of herpes simplex virus (HSV) infection. During HSV type 1 (HSV-1) infection there is a profound and rapid loss of MR1, in part due to expression of unique short 3 protein. Here we show that virion host shutoff RNase protein downregulates MR1 protein, through loss of MR1 transcripts. Furthermore, a third viral protein, infected cell protein 22, also downregulates MR1, but not classical MHC-I molecules. This occurs early in the MR1 trafficking pathway through proteasomal degradation. Finally, HSV-2 infection results in the loss of MR1 transcripts, and intracellular and surface MR1 protein, comparable to that seen during HSV-1 infection. Thus HSV coordinates a multifaceted attack on the MR1 antigen presentation pathway, potentially protecting infected cells from MAIT cell T cell receptor-mediated detection at sites of primary infection and reactivation.

Keywords: Cell biology; Immunology; Virology.

Abstract

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