title: Streptococcus pyogenes SpyCEP influences host-pathogen interactions during infection in a murine air pouch model.
abstract: Streptococcus pyogenes is a major human pathogen worldwide, responsible for both local and systemic infections. These bacteria express the subtilisin-like protease SpyCEP which cleaves human IL-8 and related chemokines. We show that localization of SpyCEP is growth-phase and strain dependent. Significant shedding was observed only in a strain naturally overexpressing SpyCEP, and shedding was not dependent on SpyCEP autoproteolytic activity. Surface-bound SpyCEP in two different strains was capable of cleaving IL-8. To investigate SpyCEP action in vivo, we adapted the mouse air pouch model of infection for parallel quantification of bacterial growth, host immune cell recruitment and chemokine levels in situ. In response to infection, the predominant cells recruited were neutrophils, monocytes and eosinophils. Concomitantly, the chemokines KC, LIX, and MIP-2 in situ were drastically increased in mice infected with the SpyCEP knockout strain, and growth of this mutant strain was reduced compared to the wild type. SpyCEP has been described as a potential vaccine candidate against S. pyogenes, and we showed that surface-associated SpyCEP was recognized by specific antibodies. In vitro, such antibodies also counteracted the inhibitory effects of SpyCEP on chemokine mediated PMN recruitment. Thus, α-SpyCEP antibodies may benefit the host both directly by enabling opsonophagocytosis, and indirectly, by neutralizing an important virulence factor. The animal model we employed shows promise for broad application in the study of bacterial pathogenesis.
authors: Research Centre, Novartis Vaccines and Diagnostics, Siena, Italy.
authors: Nico
authors: N
authors: Chiappini
authors: Anja
authors: A
authors: Seubert
authors: John L
authors: JL
authors: Telford
authors: Guido
authors: G
authors: Grandi
authors: Davide
authors: D
authors: Serruto
authors: Immaculada
authors: I
authors: Margarit
authors: Robert
authors: R
authors: Janulczyk
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D054884:Host-Pathogen Interactions; D006801:Humans; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010447:Peptide Hydrolases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D059748:Proteolysis; D013209:Staphylococcal Vaccines / Q000235:genetics / Q000276:immunology; D013290:Streptococcal Infections / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D013297:Streptococcus pyogenes / Q000502:physiology*
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D018925:Chemokines; D013209:Staphylococcal Vaccines; D010447:Peptide Hydrolases; C527349:SpyCEP protein, Streptococcus pyogenes