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Cell Host Microbe. 2016 Feb 10;19(2):216-26. doi: 10.1016/j.chom.2016.01.004.

A Bacterial Pathogen Targets a Host Rab-Family GTPase Defense Pathway with a GAP.

Author information

1
Department of Microbial Pathogenesis, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA. Electronic address: stefania.spano@abdn.ac.uk.
2
Department of Microbial Pathogenesis, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
3
Department of Microbial Pathogenesis, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA. Electronic address: jorge.galan@yale.edu.

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.

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

PMID:
26867180
PMCID:
PMC4854434
DOI:
10.1016/j.chom.2016.01.004
[Indexed for MEDLINE]
Free PMC Article

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