Coxiella burnetii is an intracellular pathogen that causes the human disease Q-fever. Mechanisms by which this bacterial pathogen exploits human cells remain unknown. This project is focused on the activities of virulence determinants in Coxiella that are essential for biogenesis of a vacuole that supports bacterial replication. One of the essential determinants for biogenesis of the Coxiella-containing vacuole (CCV) is the Dot/Icm system, which is a functional type IVb protein secretion machine that promotes infection by delivering bacterial effectors into host cells. We have identified Coxiella mutants that are deficient in effector proteins, which led to the identification of effector proteins that function n vacuole biogenesis. To understand how these effector proteins promote biogenesis of a vacuole that support Coxiella replication we will complete the following aims.
Aim 1 : Determine how Cig57 and Cig2 modulate host cell functions.
Aim 2 : Determine why host autophagy is essential for normal CCV biogenesis and fusion.
Aim 3 : Identify effector proteins that have important roles in relevant cell types.

Public Health Relevance

Intracellular pathogens represent a serious threat to human health, and to devise strategies to combat infections by these microbes a more detailed understanding of how they modulate host cell function is needed. Thus, this project is focused on determining the unique mechanisms that the intracellular pathogen Coxiella burnetii employs to modify and subvert organelles in the host cell that contribute to the destruction of microbial pathogens, which are lysosomes and autophagosomes. Understanding how Coxiella manipulates host organelles to create a vacuole that supports replication will provide needed insight into an important virulence strategy that enables intracellular pathogens to survive in hostile intracellular environments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI114760-05
Application #
9625740
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Perdue, Samuel S
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
5
Fiscal Year
2019
Total Cost
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
Crabill, Emerson; Schofield, Whitman B; Newton, Hayley J et al. (2018) Dot/Icm-Translocated Proteins Important for Biogenesis of the Coxiella burnetii-Containing Vacuole Identified by Screening of an Effector Mutant Sublibrary. Infect Immun 86:
Kohler, Lara J; Roy, Craig R (2017) Autophagic targeting and avoidance in intracellular bacterial infections. Curr Opin Microbiol 35:36-41
Kohler, Lara J; Reed, Shawna C O; Sarraf, Shireen A et al. (2016) Effector Protein Cig2 Decreases Host Tolerance of Infection by Directing Constitutive Fusion of Autophagosomes with the Coxiella-Containing Vacuole. MBio 7:
Kohler, Lara J; Roy, Craig R (2015) Biogenesis of the lysosome-derived vacuole containing Coxiella burnetii. Microbes Infect 17:766-71
Cunha, Larissa D; Ribeiro, Juliana M; Fernandes, Talita D et al. (2015) Inhibition of inflammasome activation by Coxiella burnetii type IV secretion system effector IcaA. Nat Commun 6:10205