The Type IV Secretion System Effector Protein CirA Stimulates the GTPase Activity of RhoA and Is Required for Virulence in a Mouse Model of Coxiella burnetii Infection

Coxiella burnetii, the etiological agent of Q fever in humans, is an intracellular pathogen that replicates in an acidified parasitophorous vacuole derived from host lysosomes. Generation of this replicative compartment requires effectors delivered into the host cell by the Dot/Icm type IVb secretio...

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Published in:Infection and immunity 2016-09, Vol.84 (9), p.2524-2533
Main Authors: Weber, Mary M, Faris, Robert, van Schaik, Erin J, McLachlan, Juanita Thrasher, Wright, William U, Tellez, Andres, Roman, Victor A, Rowin, Kristina, Case, Elizabeth Di Russo, Luo, Zhao-Qing, Samuel, James E
Format: Article
Language:English
Subjects:
Animals
Bacterial Proteins - metabolism
Cell Line, Tumor
Cellular Microbiology: Pathogen-Host Cell Molecular Interactions
Coxiella burnetii
Coxiella burnetii - metabolism
GTP Phosphohydrolases - metabolism
HeLa Cells
Host-Pathogen Interactions - physiology
Humans
Lysosomes - metabolism
Mice
Protein Transport - physiology
Q Fever - metabolism
Q Fever - microbiology
rhoA GTP-Binding Protein - metabolism
Type IV Secretion Systems - metabolism
Vacuoles - metabolism
Vacuoles - microbiology
Virulence - physiology
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Summary:Coxiella burnetii, the etiological agent of Q fever in humans, is an intracellular pathogen that replicates in an acidified parasitophorous vacuole derived from host lysosomes. Generation of this replicative compartment requires effectors delivered into the host cell by the Dot/Icm type IVb secretion system. Several effectors crucial for C. burnetii intracellular replication have been identified, but the host pathways coopted by these essential effectors are poorly defined, and very little is known about how spacious vacuoles are formed and maintained. Here we demonstrate that the essential type IVb effector, CirA, stimulates GTPase activity of RhoA. Overexpression of CirA in mammalian cells results in cell rounding and stress fiber disruption, a phenotype that is rescued by overexpression of wild-type or constitutively active RhoA. Unlike other effector proteins that subvert Rho GTPases to modulate uptake, CirA is the first effector identified that is dispensable for uptake and instead recruits Rho GTPase to promote biogenesis of the bacterial vacuole. Collectively our results highlight the importance of CirA in coopting host Rho GTPases for establishment of Coxiella burnetii infection and virulence in mammalian cell culture and mouse models of infection.
ISSN:0019-9567
1098-5522
DOI:10.1128/IAI.01554-15