T cell inactivation by poxviral B22 family proteins increases viral virulence

• Published in: PLoS pathogens Vol. 10; no. 5; p. e1004123
• Main Authors: Alzhanova, Dina, Hammarlund, Erika, Reed, Jason, Meermeier, Erin, Rawlings, Stephanie, Ray, Caroline A, Edwards, David M, Bimber, Ben, Legasse, Alfred, Planer, Shannon, Sprague, Jerald, Axthelm, Michael K, Pickup, David J, Lewinsohn, David M, Gold, Marielle C, Wong, Scott W, Sacha, Jonah B, Slifka, Mark K, Früh, Klaus
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2014; Public Library of Science (PLoS)
• Subjects: Animals; B cells; Biology and Life Sciences; Cells, Cultured; Chlorocebus aethiops; CHO Cells; Colleges & universities; Cricetinae; Cricetulus; Diagnosis; Disease; Experiments; Female; Genes; Genomes; HEK293 Cells; Humans; Immune Evasion - genetics; Immune system; Jurkat Cells; Lymphocytes; Macaca mulatta; Medicine; Mice; Mice, Inbred BALB C; Monkeys & apes; Mortality; Mpox (monkeypox) - immunology; Physiological aspects; Poxviridae - genetics; Poxviridae - immunology; Poxviridae - pathogenicity; Poxviridae Infections - immunology; Proteins; Risk factors; Smallpox; T cell receptors; T cells; T-Lymphocytes - immunology; T-Lymphocytes - virology; Vaccines; Viral Proteins - physiology; Virus diseases; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1004123

Infections with monkeypox, cowpox and weaponized variola virus remain a threat to the increasingly unvaccinated human population, but little is known about their mechanisms of virulence and immune evasion. We now demonstrate that B22 proteins, encoded by the largest genes of these viruses, render human T cells unresponsive to stimulation of the T cell receptor by MHC-dependent antigen presentation or by MHC-independent stimulation. In contrast, stimuli that bypass TCR-signaling are not inhibited. In a non-human primate model of monkeypox, virus lacking the B22R homologue (MPXVΔ197) caused only mild disease with lower viremia and cutaneous pox lesions compared to wild type MPXV which caused high viremia, morbidity and mortality. Since MPXVΔ197-infected animals displayed accelerated T cell responses and less T cell dysregulation than MPXV US2003, we conclude that B22 family proteins cause viral virulence by suppressing T cell control of viral dissemination.