title: A Bacterial Pathogen Targets a Host Rab-Family GTPase Defense Pathway with a GAP.
abstract: Cell-autonomous defense mechanisms are potent strategies that protect individual cells against intracellular pathogens. The Rab-family GTPase Rab32 was previously shown to restrict the intracellular human pathogen Salmonella Typhi, but its potential broader role in antimicrobial defense remains unknown. We show that Rab32 represents a general cell-autonomous, antimicrobial defense that is counteracted by two Salmonella effectors. Mice lacking Rab-32 or its nucleotide exchange factor BLOC-3 are permissive to S. Typhi infection and exhibit increased susceptibility to S. Typhimurium. S. Typhimurium counters this defense pathway by delivering two type III secretion effectors, SopD2, a Rab32 GAP, and GtgE, a specific Rab32 protease. An S. Typhimurium mutant strain lacking these two effectors exhibits markedly reduced virulence, which is fully restored in BLOC-3-deficient mice. These results demonstrate that a cell-autonomous, Rab32-dependent host defense pathway plays a central role in the defense against vacuolar pathogens and describe a mechanism evolved by a bacterial pathogen to counter it.
authors: Department of Microbial Pathogenesis, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA. Electronic address: stefania.spano@abdn.ac.uk.
authors: Stefania
authors: S
authors: Spanò
authors: Department of Microbial Pathogenesis, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
authors: Xiang
authors: X
authors: Gao
authors: Department of Microbial Pathogenesis, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
authors: Sebastian
authors: S
authors: Hannemann
authors: Department of Microbial Pathogenesis, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
authors: María
authors: M
authors: Lara-Tejero
authors: Department of Microbial Pathogenesis, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA. Electronic address: jorge.galan@yale.edu.
authors: Jorge E
authors: JE
authors: Galán
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D059748:Proteolysis; D012480:Salmonella Infections / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology; D012485:Salmonella typhi / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D012486:Salmonella typhimurium / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D014774:Virulence; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; C478766:Rab32 protein, mouse; D020691:rab GTP-Binding Proteins
keywords: Rab GTPases; Rab32; Salmonella Typhi; Salmonella pathogenesis; bacterial pathogenesis; cell-autonomous defense; innate immunity; lysosome-related organelles; lysosomes; macrophages; membrane traffic; type III secretion; typhoid fever