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Characterizing an alternative genetic pathway critical for the virulence of Brucella

Award Number: R21AI185249
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/12/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Characterizing an alternative genetic pathway critical for the virulence of Brucella - Project Summary Brucella spp. are bacteria that naturally infect a variety of domesticated and wild animals leading to abortions and sterility, and these bacteria are also capable of causing debilitating human infections, which often result from human exposure to infected animals and animal products. Brucella spp. are considered threats as potential biological weapons. Importantly, antibiotic treatment against brucellosis is prone to disease relapse, and there is currently no safe and effective vaccine to protect humans against infection with Brucella. The brucellae are intracellular pathogens that reside within immune cells called macrophages where they replicate in a specialized compartment, and the capacity of Brucella to survive and replicate within macrophages is essential to their ability to cause disease. Over the last few years, our laboratory has characterized genetic pathways that are critical for the intracellular survival and pathogenesis of Brucella strains, and specifically, we have identified a transcriptional regulator, called VtlR that is essential for Brucella virulence. Previous work in our laboratory determined that VtlR is critical for the ability of B. abortus to infect macrophages and mice, and we determined that transcriptional regulon of VtlR at that time in nutrient-replete medium. Interestingly, only four genes exhibited substantial dysregulation in a DvtlR strain; however, simultaneous deletion of these four genes did not phenocopy the virulence defect observed in the DvtlR strain. As such, we hypothesized that VtlR control the expression of an “alternative regulon” in response to a biologically relevant signal. Preliminary work has determined that the C-terminal cofactor/sensing domain of VtlR contains two cysteine residues that are critical for the virulence-linked activity of VtlR. Indeed, mutation of these cysteine residues results in a significant reduction in survival and replication of B. abortus in murine macrophages, but mutation of the cysteines does not alter the expression of the four genes previously described to be controlled by VtlR. Taken together, we predict that VtlR senses oxidative stress through these critical cysteine residues to control the expression of genes needed for the infection process, and experiments proposed in this application will test this overarching hypothesis. The exploratory studies outlined in this application are extremely well-suited for the R21 mechanism, as the data generated from these studies will set a solid foundation on which in-depth mechanistic studies can be established, and the data will form the basis for the development of a future R01 application. Additionally, the information gleaned from these studies may also be used to develop new therapeutic and vaccine strategies against human Brucella infection.


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 = $421,560 )
2026	2026	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	1	6/16/2026	NEW	$421,560
														Subtotal = $421,560

Grand Total All Awards = $421,560

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Characterizing an alternative genetic pathway critical for the virulence of Brucella

Award Number: R21AI185249

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/12/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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