title: Contribution of Asparagine Catabolism to Salmonella Virulence.
abstract: Salmonellae are pathogenic bacteria that cause significant morbidity and mortality in humans worldwide. Salmonellae establish infection and avoid clearance by the immune system by mechanisms that are not well understood. We previously showed that l-asparaginase II produced by Salmonella enterica serovar Typhimurium (S Typhimurium) inhibits T cell responses and mediates virulence. In addition, we previously showed that asparagine deprivation such as that mediated by l-asparaginase II of S Typhimurium causes suppression of activation-induced T cell metabolic reprogramming. Here, we report that STM3997, which encodes a homolog of disulfide bond protein A (dsbA) of Escherichia coli, is required for l-asparaginase II stability and function. Furthermore, we report that l-asparaginase II localizes primarily to the periplasm and acts together with l-asparaginase I to provide S Typhimurium the ability to catabolize asparagine and assimilate nitrogen. Importantly, we determined that, in a murine model of infection, S Typhimurium lacking both l-asparaginase I and II genes competes poorly with wild-type S Typhimurium for colonization of target tissues. Collectively, these results indicate that asparagine catabolism contributes to S Typhimurium virulence, providing new insights into the competition for nutrients at the host-pathogen interface.
authors.affiliation: Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: McLaughlin
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: McClelland
authors.affiliation: Department of Microbial Pathogenesis and Immunology, Texas A&M University System Health Science Center, Bryan, Texas, USA.
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Yang
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, California, USA.
authors.forename: Steffen
authors.initials: S
authors.lastname: Porwollik
authors.affiliation: Department of Microbial Pathogenesis and Immunology, Texas A&M University System Health Science Center, Bryan, Texas, USA.
authors.forename: Lydia
authors.initials: L
authors.lastname: Bogomolnaya
authors.affiliation: Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Juei-Suei
authors.initials: JS
authors.lastname: Chen
authors.affiliation: Department of Microbial Pathogenesis and Immunology, Texas A&M University System Health Science Center, Bryan, Texas, USA.
authors.forename: Helene
authors.initials: H
authors.lastname: Andrews-Polymenis
authors.affiliation: Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Stony Brook University, Stony Brook, New York, USA a.vandervelden@stonybrook.edu.
authors.forename: Adrianus W M
authors.initials: AWM
authors.lastname: van der Velden
mesh_terms: D000818:Animals; D001215:Asparaginase / Q000378:metabolism; D001216:Asparagine / Q000378:metabolism*; D002384:Catalysis; D003545:Cysteine / Q000378:metabolism; D004195:Disease Models, Animal; D004795:Enzyme Stability; D005260:Female; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D009154:Mutation; D009584:Nitrogen / Q000378:metabolism; D012475:Salmonella / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity*; D012480:Salmonella Infections / Q000382:microbiology*; D012481:Salmonella Infections, Animal / Q000382:microbiology; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics
chemical_list: D037521:Virulence Factors; D001216:Asparagine; D001215:Asparaginase; D003545:Cysteine; D009584:Nitrogen
keywords: Salmonella; T cells; asparaginase; asparagine; catabolism; host response; metabolism; nitrogen metabolism; pathogenesis; virulence