Coxiella burnetii is an obligate intracellular pathogen that grows within a specialized vacuole that is derived from fusion with lysosomes. Coxiella proteins that participate in the creation of this unique compartment and that modulate host cell functions are unknown. It has been proposed that a Cox/e//a-encoded type IVB protein secretion system is involved in host pathogenesis. The Coxiella type IVB system is functionally related to the Dot/lcm system found in the intracellular pathogen Legionella pneumophila. The similarity between these two bacterial type IV secretion systems has been exploited to identify Coxiella proteins that are translocated into eukaryotic host cells by the Legionella Dot/lcm system. The Coxiella proteins identified as substrates of the Dot/lcm system all contain multiple ankyrin-repeat domains, which are protein-protein interaction domains found in many eukaryotic proteins. The hypothesis to be tested is that these Coxiella Ank proteins are Dot/lcm substrates translocated into host cells during Coxiella infection and that these Ank proteins are directly involved in modulation of host cell functions. Examining the localization Ank proteins in cells infected with Coxiella will test whether these proteins are translocated. Ectopic production of Ank proteins in eukaryotic host cells will reveal host processes that are affected by Ank proteins. Cellular targets for the Ank proteins will be determined and additional substrates of the Coxiella Dot/lcm system will be identified using genetic and molecular approaches. These studies will elucidate pathogenic determinants that allow host cell infection by Coxiella and reveal intracellular infection strategies employed by this important pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064559-05
Application #
7750032
Study Section
Special Emphasis Panel (ZRG1-IDM-J (04))
Program Officer
Perdue, Samuel S
Project Start
2006-01-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
5
Fiscal Year
2010
Total Cost
$346,916
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kohler, Lara J; Roy, Craig R (2017) Autophagic targeting and avoidance in intracellular bacterial infections. Curr Opin Microbiol 35:36-41
Newton, Hayley J; Kohler, Lara J; McDonough, Justin A et al. (2014) A screen of Coxiella burnetii mutants reveals important roles for Dot/Icm effectors and host autophagy in vacuole biogenesis. PLoS Pathog 10:e1004286
McDonough, Justin A; Newton, Hayley J; Klum, Scott et al. (2013) Host pathways important for Coxiella burnetii infection revealed by genome-wide RNA interference screening. MBio 4:e00606-12
Newton, Hayley J; McDonough, Justin A; Roy, Craig R (2013) Effector protein translocation by the Coxiella burnetii Dot/Icm type IV secretion system requires endocytic maturation of the pathogen-occupied vacuole. PLoS One 8:e54566
Hardiman, Camille A; McDonough, Justin A; Newton, Hayley J et al. (2012) The role of Rab GTPases in the transport of vacuoles containing Legionella pneumophila and Coxiella burnetii. Biochem Soc Trans 40:1353-9
Mukherjee, Shaeri; Liu, Xiaoyun; Arasaki, Kohei et al. (2011) Modulation of Rab GTPase function by a protein phosphocholine transferase. Nature 477:103-6
Alix, Eric; Mukherjee, Shaeri; Roy, Craig R (2011) Subversion of membrane transport pathways by vacuolar pathogens. J Cell Biol 195:943-52
Carey, Kimberly L; Newton, Hayley J; Luhrmann, Anja et al. (2011) The Coxiella burnetii Dot/Icm system delivers a unique repertoire of type IV effectors into host cells and is required for intracellular replication. PLoS Pathog 7:e1002056
Newton, Hayley J; Roy, Craig R (2011) The Coxiella burnetii Dot/Icm system creates a comfortable home through lysosomal renovation. MBio 2:
Cossart, Pascale; Roy, Craig R (2010) Manipulation of host membrane machinery by bacterial pathogens. Curr Opin Cell Biol 22:547-54

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