THEMIS is Required for Pathogenesis of Cerebral Malaria and for Protection against Pulmonary Tuberculosis

Sabrina Torre (PhD.4)^*,†, Sebastien P. Faucher^†,‡, Nassima Fodil^†,§, Silayuv E. Bongfen^†,§, Joanne Berghout^†,§, Jeremy A. Schwartzentruber^*,¶, Jacek Majewski^*,¶, Mark Lathrop^*,¶, Andrea M. Cooper^||, Silvia M. Vidal^*,†,‡, and Philippe Gros^*,†,§

*Department of Human Genetics, McGill University, Montreal, QC, Canada; †Complex Traits Group, McGill University, Montreal, QC, Canada; ‡Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada; §Department of Biochemistry, McGill University, Montreal, QC, Canada; ¶McGill and Genome Quebec Innovation Center, McGill University, Montreal, QC, Canada; ||Trudeau Institute Inc., Saranac Lake, New York, United States of America.

We identify an N-ethyl-N-nitrosourea (ENU)-induced I23N mutation in the THEMIS protein that causes protection against experimental cerebral malaria (ECM) caused by infection with Plasmodium berghei ANKA (PbA). Themis^I23N homozygote mice show reduced CD4⁺ and CD8⁺ T lymphocyte numbers. ECM-resistance in PbA-infected Themis^I23N mice is associated with decreased cerebral cellular infiltration, retention of blood-brain barrier integrity, and reduced pro-inflammatory cytokine production. THEMIS^I23N protein expression is absent in mutant mice, concurrent with decreased THEMIS^I23N stability observed in vitro. Biochemical studies in vitro, and functional complementation in vivo in Themis^I23N/+:Lck^-/+ double-heterozygotes demonstrate that functional coupling of THEMIS to LCK tyrosine kinase is required for ECM pathogenesis. Dampening of pro-inflammatory responses in Themis^I23N mice causes susceptibility to pulmonary tuberculosis. Thus, THEMIS is required for development, and ultimately function of pro-inflammatory T cells. Themis^I23N mice can be used to study the newly discovered association of THEMIS (6p22.33) with inflammatory bowel disease, and multiple sclerosis.