title: L-asparaginase II produced by Salmonella typhimurium inhibits T cell responses and mediates virulence.
abstract: Salmonella enterica serovar Typhimurium avoids clearance by the host immune system by suppressing T cell responses; however, the mechanisms that mediate this immunosuppression remain unknown. We show that S. Typhimurium inhibit T cell responses by producing L-Asparaginase II, which catalyzes the hydrolysis of L-asparagine to aspartic acid and ammonia. L-Asparaginase II is necessary and sufficient to suppress T cell blastogenesis, cytokine production, and proliferation and to downmodulate expression of the T cell receptor. Furthermore, S. Typhimurium-induced inhibition of T cells in vitro is prevented upon addition of L-asparagine. S. Typhimurium lacking the L-Asparaginase II gene (STM3106) are unable to inhibit T cell responses and exhibit attenuated virulence in vivo. L-Asparaginases are used to treat acute lymphoblastic leukemia through mechanisms that likely involve amino acid starvation of leukemic cells, and these findings indicate that pathogens similarly use L-asparagine deprivation to limit T cell responses.
authors.affiliation: Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11794-5120, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Kullas
authors.forename: Michael
authors.initials: M
authors.lastname: McClelland
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Yang
authors.forename: Jason W
authors.initials: JW
authors.lastname: Tam
authors.forename: AnnMarie
authors.initials: A
authors.lastname: Torres
authors.forename: Steffen
authors.initials: S
authors.lastname: Porwollik
authors.forename: Patricio
authors.initials: P
authors.lastname: Mena
authors.forename: Joseph B
authors.initials: JB
authors.lastname: McPhee
authors.forename: Lydia
authors.initials: L
authors.lastname: Bogomolnaya
authors.forename: Helene
authors.initials: H
authors.lastname: Andrews-Polymenis
authors.forename: Adrianus W M
authors.initials: AW
authors.lastname: van der Velden
mesh_terms: D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001215:Asparaginase / Q000235:genetics / Q000378:metabolism*; D001216:Asparagine / Q000378:metabolism; D001224:Aspartic Acid / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D017353:Gene Deletion; D057131:Immune Evasion; D051379:Mice; D008810:Mice, Inbred C57BL; D012486:Salmonella typhimurium / Q000201:enzymology* / Q000276:immunology / Q000472:pathogenicity*; D013601:T-Lymphocytes / Q000276:immunology*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D037521:Virulence Factors; D001224:Aspartic Acid; D001216:Asparagine; D000641:Ammonia; D001215:Asparaginase