title: Salmonella enterica serovar Typhimurium mutants unable to convert malate to pyruvate and oxaloacetate are avirulent and immunogenic in BALB/c mice.
abstract: Previously, we showed that the Salmonella enterica serovar Typhimurium SR-11 tricarboxylic acid (TCA) cycle must operate as a complete cycle for full virulence after oral infection of BALB/c mice (M. Tchawa Yimga, M. P. Leatham, J. H. Allen, D. C. Laux, T. Conway, and P. S. Cohen, Infect. Immun. 74:1130-1140, 2006). In the same study, we showed that for full virulence, malate must be converted to both oxaloacetate and pyruvate. Moreover, it was recently demonstrated that blocking conversion of succinyl-coenzyme A to succinate attenuates serovar Typhimurium SR-11 but does not make it avirulent; however, blocking conversion of succinate to fumarate renders it completely avirulent and protective against subsequent oral infection with the virulent serovar Typhimurium SR-11 wild-type strain (R. Mercado-Lubo, E. J. Gauger, M. P. Leatham, T. Conway, and P. S. Cohen, Infect. Immun. 76:1128-1134, 2008). Furthermore, the ability to convert succinate to fumarate appeared to be required only after serovar Typhimurium SR-11 became systemic. In the present study, evidence is presented that serovar Typhimurium SR-11 mutants that cannot convert fumarate to malate or that cannot convert malate to both oxaloacetate and pyruvate are also avirulent and protective in BALB/c mice. These results suggest that in BALB/c mice, the malate that is removed from the TCA cycle in serovar Typhimurium SR-11 for conversion to pyruvate must be replenished by succinate or one of its precursors, e.g., arginine or ornithine, which might be available in mouse phagocytes.
authors.affiliation: Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 028811, USA.
authors.forename: Regino
authors.initials: R
authors.lastname: Mercado-Lubo
authors.forename: Mary P
authors.initials: MP
authors.lastname: Leatham
authors.forename: Tyrrell
authors.initials: T
authors.lastname: Conway
authors.forename: Paul S
authors.initials: PS
authors.lastname: Cohen
mesh_terms: D000818:Animals; D002952:Citric Acid Cycle; D003470:Culture Media; D005260:Female; D005650:Fumarates / Q000378:metabolism; D008293:Malates / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D062907:Oxaloacetic Acid / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism*; D012480:Salmonella Infections / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D012486:Salmonella typhimurium / Q000235:genetics / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity; D013386:Succinates / Q000378:metabolism; D014774:Virulence
chemical_list: D003470:Culture Media; D005650:Fumarates; D008293:Malates; D013386:Succinates; D062907:Oxaloacetic Acid; C030298:malic acid; D019289:Pyruvic Acid