Genome-wide mouse mutagenesis reveals CD45-mediated T cell function as critical in protective immunity to HSV-1.
Herpes simplex encephalitis (HSE) is a lethal neurological disease resulting from infection with Herpes Simplex Virus 1 (HSV-1). Loss-of-function mutations in the UNC93B1, TLR3, TRIF, TRAF3, and TBK1 genes have been associated with a human genetic predisposition to HSE, demonstrating the UNC93B-TLR3-type I IFN pathway as critical in protective immunity to HSV-1. However, the TLR3, UNC93B1, and TRIF mutations exhibit incomplete penetrance and represent only a minority of HSE cases, perhaps reflecting the effects of additional host genetic factors. In order to identify new host genes, proteins and signaling pathways involved in HSV-1 and HSE susceptibility, we have implemented the first genome-wide mutagenesis screen in an in vivo HSV-1 infectious model. One pedigree (named P43) segregated a susceptible trait with a fully penetrant phenotype. Genetic mapping and whole exome sequencing led to the identification of the causative nonsense mutation L3X in the Receptor-type tyrosine-protein phosphatase C gene (Ptprc(L3X)), which encodes for the tyrosine phosphatase CD45. Expression of MCP1, IL-6, MMP3, MMP8, and the ICP4 viral gene were significantly increased in the brain stems of infected Ptprc(L3X) mice accounting for hyper-inflammation and pathological damages caused by viral replication. Ptprc(L3X) mutation drastically affects the early stages of thymocytes development but also the final stage of B cell maturation. Transfer of total splenocytes from heterozygous littermates into Ptprc(L3X) mice resulted in a complete HSV-1 protective effect. Furthermore, T cells were the only cell population to fully restore resistance to HSV-1 in the mutants, an effect that required both the CD4⁺ and CD8⁺ T cells and could be attributed to function of CD4⁺ T helper 1 (Th1) cells in CD8⁺ T cell recruitment to the site of infection. Altogether, these results revealed the CD45-mediated T cell function as potentially critical for infection and viral spread to the brain, and also for subsequent HSE development.
Departments of Human Genetics and Medicine, McGill University, Montréal, Quebec, Canada.
Grégory
G
Caignard
Gabriel A
GA
Leiva-Torres
Michael
M
Leney-Greene
Benoit
B
Charbonneau
Anne
A
Dumaine
Nassima
N
Fodil-Cornu
Michal
M
Pyzik
Pablo
P
Cingolani
Jeremy
J
Schwartzentruber
Jeremy
J
Dupaul-Chicoine
Huaijian
H
Guo
Maya
M
Saleh
André
A
Veillette
Marc
M
Lathrop
Mathieu
M
Blanchette
Jacek
J
Majewski
Angela
A
Pearson
Silvia M
SM
Vidal
D000818:Animals; D001933:Brain Stem / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002478:Cells, Cultured; D018389:Codon, Nonsense; D003433:Crosses, Genetic; D004198:Disease Susceptibility; D020803:Encephalitis, Herpes Simplex / Q000209:etiology / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006561:Herpes Simplex / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D007111:Immunity, Cellular; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016019:Survival Analysis; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology
D018389:Codon, Nonsense; D009419:Nerve Tissue Proteins; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse