title: Antiprotease inactivation by Salmonella enterica released from infected macrophages.
abstract: The mammalian serine protease plasmin, which has an important role in extracellular matrix degradation during cell migration, is regulated by the plasma antiprotease alpha(2)-antiplasmin (alpha(2)AP). The surface protease PgtE of Salmonella enterica serovar Typhimurium proteolytically inactivated alpha(2)AP. PgtE also activates the plasma zymogen plasminogen to plasmin, and bacteria expressing PgtE promoted degradation of extracellular matrix laminin in the presence of plasminogen and alpha(2)AP. alpha(2)AP inactivation was detected with the rough derivative of S. enterica 14028, but not with the smooth wild-type strain, suggesting that the O-antigen of lipopolysaccharide prevented contact of PgtE with the substrate molecule. After growth of S. enterica 14028 in murine J774A.1 macrophage-like cells, the infected cell lysate as well as bacteria from isolated Salmonella-containing vacuoles (SCVs) cleaved alpha(2)AP. Bacteria from SCVs produced an elevated level of PgtE and had a reduced O-antigen chain length. The lysate from S. enterica 14028-infected macrophages promoted formation of plasmin in the presence of alpha(2)AP, whereas plasmin formation by lysates from uninfected macrophages, or from macrophages infected with the pgtE-negative derivative of 14028, was inhibited by alpha(2)AP. Salmonella disseminates in the host within macrophages, which utilize plasmin for migration through tissue barriers. The results suggest that intracellular enhancement of PgtE activity in Salmonella may promote macrophage-associated proteolysis and cellular migration by altering the balance between host plasmin and alpha(2)AP.
authors.affiliation: General Microbiology, Faculty of Biosciences, University of Helsinki, Helsinki, Finland. Kaarina.Lahteenmaki@helsinku.fi
authors.forename: Kaarina
authors.initials: K
authors.lastname: Lähteenmäki
authors.forename: Päivi
authors.initials: P
authors.lastname: Kyllönen
authors.forename: Lotta
authors.initials: L
authors.lastname: Partanen
authors.forename: Timo K
authors.initials: TK
authors.lastname: Korhonen
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D010587:Phagocytosis; D012486:Salmonella typhimurium / Q000201:enzymology* / Q000472:pathogenicity* / Q000648:ultrastructure; D014617:Vacuoles; D000979:alpha-2-Antiplasmin / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D000979:alpha-2-Antiplasmin; D010450:Endopeptidases; C411337:PgtE protein, Salmonella enterica; D005341:Fibrinolysin