Roles of Salmonella enterica serovar Typhimurium encoded Peptidase N during systemic infection of Ifnγ-/- mice

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-gamma (IFN gamma), a cytokine important for immunity. S. typhimurium lacking pepN (Delta pepN) displays enhanced colony forming units (CFU) compared to WT in peripheral organs during systemic infection in C57BL/6 mice. However, Ifn gamma(-/-) mice show higher CFU compared to C57BL/6 mice, resulting in lower fold differences between WT and Delta pepN. Concomitantly, reintroduction of pepN in Delta pepN (Delta pepN/pepN) reduces CFU, demonstrating pepN-dependence. Interestingly, expression of a catalytically inactive PepN (Delta pepN/E298A) also lowers CFU, demonstrating that the decrease in CPU is independent of the catalytic activity of PepN. In addition, three distinct differences are observed between infection of C57BL/6 and Ifn gamma(-/-) mice: First, serum amounts of TNF alpha and IL1 beta post infection are significantly lower in Ifn gamma(-/-) mice. Second, histological analysis of C57BL16 mice reveals that damage in spleen and liver upon infection with WT or Delta pepN is greater compared to Delta pepN/pepN or Delta pepN/E298A. On the other hand, Ifn gamma(-/-) 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 Ifn gamma(-/-) mice, is observed upon infection with Delta pepN/pepN or Delta pepN/E298A. Overall, the roles of the host encoded IFN gamma during infection with S. typhimurium strains with varying degrees of virulence are highlighted. (C) 2011 Elsevier GmbH. All rights reserved.