T cell inactivation by poxviral B22 family proteins increases viral virulence.
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.
Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Dina
D
Alzhanova
Division of Neuroscience, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Erika
E
Hammarlund
Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Jason
J
Reed
Department of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, Oregon, United States of America; Portland Veterans Administration Medical Center, Portland, Oregon, United States of America.
Erin
E
Meermeier
Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Stephanie
S
Rawlings
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America.
Caroline A
CA
Ray
Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Portland, Oregon, United States of America.
David M
DM
Edwards
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Ben
B
Bimber
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Alfred
A
Legasse
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Shannon
S
Planer
Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Jerald
J
Sprague
Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Portland, Oregon, United States of America; Division of Pathobiology and Immunology, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Michael K
MK
Axthelm
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America.
David J
DJ
Pickup
Department of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, Oregon, United States of America; Portland Veterans Administration Medical Center, Portland, Oregon, United States of America.
David M
DM
Lewinsohn
Department of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, Oregon, United States of America; Portland Veterans Administration Medical Center, Portland, Oregon, United States of America.
Marielle C
MC
Gold
Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Portland, Oregon, United States of America; Division of Pathobiology and Immunology, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Scott W
SW
Wong
Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Portland, Oregon, United States of America; Division of Pathobiology and Immunology, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Jonah B
JB
Sacha
Division of Neuroscience, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Mark K
MK
Slifka
Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Portland, Oregon, United States of America; Division of Pathobiology and Immunology, Oregon National Primate Research Center, Portland, Oregon, United States of America.
Klaus
K
Früh
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D057131:Immune Evasion / Q000235:genetics; D019169:Jurkat Cells; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D045908:Mpox, Monkeypox / Q000276:immunology; D011212:Poxviridae / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D011213:Poxviridae Infections / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D014764:Viral Proteins / Q000502:physiology*
D014764:Viral Proteins