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The role of a Coxiella burnetii effector protein that inhibits RIG-I signaling

Award Number: F30AI181493
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/16/2024
PERIOD OF PERFORMANCE END DATE: 01/15/2028

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The role of a Coxiella burnetii effector protein that inhibits RIG-I signaling - Project Summary/Abstract Coxiella burnetii is an obligate intracellular bacterial pathogen that grows within a lysosome-derived vacuole. The formation of a replication-permissive vacuole by C. burnetii requires a type IVB secretion system called Dot/Icm, and the >130 effector proteins delivered by this system into the host cell. While it is established that the collective activities of these effector proteins remodel host signaling networks to create a replication- permissive environment, the molecular targets and biochemical mechanisms of most of these effectors are not known. My studies have established that C. burnetii inhibits the activation of the host RIG-I pathway, a cytosolic double-stranded RNA sensing pathway, and that this process requires two effectors, EmcA and EmcB. Although these proteins do not have predicted sequence or structural homology that would indicate possible biochemical functions, we established that EmcB has cysteine deubiquitinase activity. EmcB directly targets RIG-I and preferentially cleaves long, K63-linked ubiquitin chains that are potent activators of RIG-I signaling. The goal of this study is to determine how EmcB functions to cleave ubiquitin chains from RIG-I during infection and identify how C. burnetii infection is sensed by RIG-I. To achieve this goal, I will use biochemical assays, pull-down experiments, and infection studies using a newly engineered emcA, emcB double mutant to determine how EmcB functions to inhibit the RIG-I pathway during infection (Aim 1). Next, I will identify the specific RNAs sensed by RIG-I during C. burnetii infection and test the relative capacity of these RNAs to activate the RIG-I pathway (Aim 2). Together, these studies will enhance our understanding of how intracellular bacterial pathogens modulate host signaling networks for productive infection. By understanding the molecular details of how an intracellular pathogen modulates host processes, fundamental details of C. burnetii infection will be uncovered which could provide insights that lead to improved treatments. These studies will be complemented by a rigorous and comprehensive program of professional training, clinical training, and scientific skill building to provide preparations necessary to pursue a career as a physician- scientist investigating molecular mechanisms of microbial pathogenesis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $57,538 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	3	1/2/2026	NON-COMPETING CONTINUATION	$57,538
														Subtotal = $57,538

Issue Date FY: 2025 ( Subtotal = $37,486 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	2	12/18/2024	NON-COMPETING CONTINUATION	$36,922
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	001	2	8/4/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $37,486

Issue Date FY: 2024 ( Subtotal = $36,922 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	1	11/20/2023	NEW	$32,642
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	002	1	5/16/2024	NEW	$1,280
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	003	1	9/20/2024	SUPPLEMENT FOR EXPANSION	$3,000
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	001	1	11/20/2023	NEW	$0
														Subtotal = $36,922

Grand Total All Awards = $131,946

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The role of a Coxiella burnetii effector protein that inhibits RIG-I signaling

Award Number: F30AI181493

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/16/2024

PERIOD OF PERFORMANCE END DATE: 01/15/2028

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