title: Roles of Salmonella enterica serovar Typhimurium encoded Peptidase N during systemic infection of Ifnγ-/- mice.
abstract: Pathogen encoded peptidases are known to be important during infection; however, their roles in modulating host responses in immunocompromised individuals are not well studied. The roles of S. typhimurium (WT) encoded Peptidase N (PepN), a major aminopeptidase and sole M1 family member, was studied in mice lacking Interferon-γ (IFNγ), a cytokine important for immunity. S. typhimurium lacking pepN (ΔpepN) displays enhanced colony forming units (CFU) compared to WT in peripheral organs during systemic infection in C57BL/6 mice. However, Ifnγ(-/-) mice show higher CFU compared to C57BL/6 mice, resulting in lower fold differences between WT and ΔpepN. Concomitantly, reintroduction of pepN in ΔpepN (ΔpepN/pepN) reduces CFU, demonstrating pepN-dependence. Interestingly, expression of a catalytically inactive PepN (ΔpepN/E298A) also lowers CFU, demonstrating that the decrease in CFU is independent of the catalytic activity of PepN. In addition, three distinct differences are observed between infection of C57BL/6 and Ifnγ(-/-) mice: First, serum amounts of TNFα and IL1β post infection are significantly lower in Ifnγ(-/-) mice. Second, histological analysis of C57BL/6 mice reveals that damage in spleen and liver upon infection with WT or ΔpepN is greater compared to ΔpepN/pepN or ΔpepN/E298A. On the other hand, Ifnγ(-/-) mice are highly susceptible to organ damage by all strains of S. typhimurium used in this study. Finally, greater survival of C57BL/6, but not Ifnγ(-/-) mice, is observed upon infection with ΔpepN/pepN or ΔpepN/E298A. Overall, the roles of the host encoded IFNγ during infection with S. typhimurium strains with varying degrees of virulence are highlighted.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Bhosale
authors.forename: Jayachandra C
authors.initials: JC
authors.lastname: Kadthur
authors.forename: Dipankar
authors.initials: D
authors.lastname: Nandi
mesh_terms: D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002384:Catalysis; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics; D006358:Hot Temperature; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053583:Interleukin-1beta / Q000097:blood; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000276:immunology* / Q000382:microbiology* / Q000401:mortality; D012486:Salmonella typhimurium / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D013312:Stress, Physiological; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000626:Aminopeptidases; C034113:peptidase N