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Determining the molecular basis of gene silencing by MucR and defining its role in Brucella virulence

Award Number: R01AI172822
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY Brucella spp. cause one of the world’s leading zoonotic diseases and are a major public health threat in areas of the world where brucellosis is endemic in food animals. The Zn finger protein MucR is a global regulator and essential virulence determinant in Brucella, but precisely how MucR contributes to virulence is unresolved. Studies in our laboratory have provided compelling evidence that MucR is a novel type of H-NS- like gene silencer and identified multiple virulence genes that are direct targets of MucR repression. H-NS and H-NS-like gene silencers play critical roles in coordinating the proper temporal expression of virulence genes in other bacterial pathogens. This tight regulation is crucial because the gratuitous expression of virulence genes causes fitness defects that can lead to attenuation in the host. The studies described in this application will use genetic and biochemical approaches to – a) directly test the hypothesis that MucR is a novel type of H-NS-like gene silencer; b) identify the antagonistic transcriptional activators that serve as ‘counter-silencers’ and override MucR-silencing of specific Brucella virulence genes; and c) test the hypothesis that coordinated regulation of specific virulence genes by MucR/counter-silencer pairs is required for the wild-type virulence of B. abortus 2308 in mice and cultured mammalian cells. The same biochemical properties that allow H-NS and H-NS-like proteins to serve as gene silencers also allow them to play major roles in condensing bacterial chromosomes and maintaining nucleoid structure. We have recently used chromosome conformation capture studies (Hi-C) to show that MucR also has nucleoid-structuring activity, and we plan to use this approach in combination with global and gene-specific transcriptional analysis to evaluate the impact that MucR’s nucleoid- structuring activity has on its capacity to function as a gene silencer. Our proposed research will provide a much better understanding of how MucR functions as a genetic regulator and virulence determinant in Brucella. It will also allow us to further examine a previously uncharacterized role for a Zn finger protein in prokaryotic biology.


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: 2024 ( Subtotal = $581,515 )
2024	2024	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Allergy and Infectious Diseases Research	001	2	6/10/2024	NON-COMPETING CONTINUATION	$581,515
2024	2023	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Allergy and Infectious Diseases Research	000	1	10/18/2023	NEW	$0
														Subtotal = $581,515

Issue Date FY: 2023 ( Subtotal = $594,265 )
2023	2023	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Allergy and Infectious Diseases Research	000	1	7/14/2023	NEW	$594,265
														Subtotal = $594,265

Grand Total All Awards = $1,175,780

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Determining the molecular basis of gene silencing by MucR and defining its role in Brucella virulence

Award Number: R01AI172822

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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