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Identifying host human products responsible for natural transformation of resistance traits in Acinetobacter spp

Award Number: SC3GM125556
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project summary/Abstract In recent years, a massive increase in the emergence of antibiotic resistant bacteria has been observed in clinical settings. Acinetobacter baumannii is one of the most widespread pathogens that cause these alarming infections. This bacterium is characterized by its extreme genome plasticity, facilitated by horizontal genetic transfer (HGT) processes. These characteristics are the cause of A. baumannii's remarkable ability to acquire antibiotic-resistance genes. Despite the relevance of foreign DNA acquisition to the pathobiology of A. baumannii, efforts to elucidate the mechanism/s involved in natural transformation have been scarce. We have recently demonstrated that the presence of human serum albumin (HSA) in extracellular host fluids correlates with an increase in A. baumannii natural transformation. We have also observed that the expression of the A. baumannii transcriptional regulator H-NS drops in response to HSA and that competence-associated gene expression increases in the h-ns mutant strains. This observation suggests that changes in cell's H-NS levels may play a central role in natural transformation. Hence, we hypothesize that the interaction of HSA with bacterial surface components triggers a regulatory signaling cascade that decreases H-NS expression, resulting in enhanced expression of genes involved in natural competence. To test this hypothesis, we will examine the interaction of HSA with A. baumannii cell surface proteins using the receptor activity- directed affinity tagging (re-tagging) technique (aim 1). To better understand the transcriptional response cascade responsible for HSA-mediated increase in transformation efficiency, we will determine the H-NS regulated genes associated with competence using complementary RNA-seq and ChIP-seq analyses in wild-type or h-ns mutants (aim 2). The studies proposed in this application will shed light on host adaptation processes leading to antibiotic resistance in this challenging pathogen of increasing relevance worldwide. We will provide new insights into bacterial components acting at the top of the HSA signaling cascade and H-NS's role in HSA-mediated transcriptional responses, leading to an increase in DNA-uptake. Future studies can then use these findings to develop novel approaches to treat severe Acinetobacter human infections, particularly those caused by emerging multidrug-resistant isolates.


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 = $0 )
2024	2022	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 N STATE COLLEGE BLVD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	001	5	10/17/2023	COMPETING CONTINUATION	$27,284
2024	2021	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 N STATE COLLEGE BLVD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	4	10/17/2023	NON-COMPETING CONTINUATION	-$27,284
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $106,500 )
2023	2023	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 N STATE COLLEGE BLVD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	6	6/26/2023	NON-COMPETING CONTINUATION	$106,500
														Subtotal = $106,500

Issue Date FY: 2022 ( Subtotal = $106,500 )
2022	2022	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	001	5	6/30/2022	COMPETING CONTINUATION	$106,500
2022	2021	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	4	6/20/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $106,500

Issue Date FY: 2021 ( Subtotal = $106,500 )
2021	2021	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	001	4	2/17/2021	NON-COMPETING CONTINUATION	$10,650
2021	2021	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	4	1/29/2021	NON-COMPETING CONTINUATION	$95,850
														Subtotal = $106,500

Issue Date FY: 2020 ( Subtotal = $106,500 )
2020	2020	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	001	3	3/16/2020	NON-COMPETING CONTINUATION	$10,650
2020	2020	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	3	1/31/2020	NON-COMPETING CONTINUATION	$95,850
														Subtotal = $106,500

Issue Date FY: 2019 ( Subtotal = $106,500 )
2019	2019	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	2	1/28/2019	NON-COMPETING CONTINUATION	$106,500
														Subtotal = $106,500

Issue Date FY: 2018 ( Subtotal = $105,875 )
2018	2018	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	1	2/7/2018	NEW	$105,875
														Subtotal = $105,875

Grand Total All Awards = $638,375

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Identifying host human products responsible for natural transformation of resistance traits in Acinetobacter spp

Award Number: SC3GM125556

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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