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 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.
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College of Medicine, Bryan, Texas, USA.
Mary M
MM
Weber
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College of Medicine, Bryan, Texas, USA.
Robert
R
Faris
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College of Medicine, Bryan, Texas, USA.
Erin J
EJ
van Schaik
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College of Medicine, Bryan, Texas, USA.
Juanita Thrasher
JT
McLachlan
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College of Medicine, Bryan, Texas, USA.
William U
WU
Wright
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College of Medicine, Bryan, Texas, USA.
Andres
A
Tellez
Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA.
Victor A
VA
Roman
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College of Medicine, Bryan, Texas, USA.
Kristina
K
Rowin
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College of Medicine, Bryan, Texas, USA.
Elizabeth Di Russo
ED
Case
Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA.
Zhao-Qing
ZQ
Luo
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College of Medicine, Bryan, Texas, USA jsamuel@medicine.tamhsc.edu.
James E
JE
Samuel
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D016997:Coxiella burnetii / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D021381:Protein Transport / Q000502:physiology; D011778:Q Fever / Q000378:metabolism* / Q000382:microbiology; D000069319:Type IV Secretion Systems / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism / Q000382:microbiology; D014774:Virulence / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D001426:Bacterial Proteins; D000069319:Type IV Secretion Systems; D020558:GTP Phosphohydrolases; D020742:rhoA GTP-Binding Protein