title: M1 protein-dependent intracellular trafficking promotes persistence and replication of Streptococcus pyogenes in macrophages.
abstract: Streptococcus pyogenes is an important human pathogen that causes a variety of diseases including life-threatening invasive diseases, such as toxic shock and deep tissue infections. Although S. pyogenes are classically considered extracellular pathogens, a clinical significance of an intracellular source has been emphasized. In patients with deep tissue infections, an intracellular reservoir of S. pyogenes within macrophages was shown to contribute to prolonged bacterial persistence. Here we demonstrate that intracellular survival of S. pyogenes in macrophages is associated with an M1 protein-dependent intracellular trafficking in the phagosomal-lysosomal pathway, which results in impaired fusion with lysosomes. The phagocytic vacuoles harbouring M1 protein-expressing bacteria not only served as a safe haven for the bacteria, but also as a replicating niche. An M1 protein-dependent modulation of macrophages was further supported by differences in NF-κB signalling between cells infected with either the wild-type or M1 protein-deficient strains, thereby indicating a suppressed inflammatory response when M1 protein was involved. Evidence of egress of bacteria out of their host cell and subsequent re-infection of new cells emphasize the importance of intracellular bacteria as a reservoir for dissemination of infection and continued tissue injury.
authors.affiliation: Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erika
authors.initials: E
authors.lastname: Hertzén
authors.forename: Linda
authors.initials: L
authors.lastname: Johansson
authors.forename: Robert
authors.initials: R
authors.lastname: Wallin
authors.forename: Heike
authors.initials: H
authors.lastname: Schmidt
authors.forename: Mirko
authors.initials: M
authors.lastname: Kroll
authors.forename: Anders P
authors.initials: AP
authors.lastname: Rehn
authors.forename: Malak
authors.initials: M
authors.lastname: Kotb
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Anna
authors.initials: A
authors.lastname: Norrby-Teglund
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004269:DNA, Bacterial / Q000096:biosynthesis*; D004197:Disease Reservoirs / Q000382:microbiology; D006801:Humans; D057131:Immune Evasion; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008561:Membrane Fusion / Q000235:genetics; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D013290:Streptococcal Infections / Q000276:immunology* / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000472:pathogenicity / Q000502:physiology*
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D004269:DNA, Bacterial; D050505:Mutant Proteins; D016328:NF-kappa B; C014689:streptococcal M protein