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Systems Epigenomics of Persistent Bloodstream Infection

Award Number: U19AI172713
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/10/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Systems Epigenomics of Persistent Bloodstream Infection - PROJECT ABSTRACT Persistent bloodstream infections are life-threatening infectious disease emergencies posing significant challenges to effective treatment. Such infections occur when a pathogen is susceptible to an anti-infective agent in vitro but is not cleared from the bloodstream in vivo when that anti-infective agent is used appropriately. As a result, anti-infective usage increases, accelerating alarming increases in anti-infective resistance. This vicious cycle of persistence driving anti- infective escalation driving resistance is an NIH high–priority concern. Bloodstream infections caused by Staphylococcus aureus (SA) or Candida albicans (CA) are increasingly common. Of urgent concern, up to 35% of patients with methicillin-resistant SA (MRSA) persistent bacteremia succumb even on gold-standard therapy. Likewise, in patients with hematogenously disseminated candidiasis (HDC), mortality is 39% overall and 47% in those in the intensive care unit, despite appropriate treatment. A disease mystery is central to such infections: the causative pathogen is susceptible to antimicrobials in laboratory testing—but not in the human being. Importantly, persistence reflects a unique type of treatment-refractory infections distinct from classical antibiotic resistance. Rather, persistent MRSA or CA are elusive: they adapt to host immune responses and antibiotic stresses uniquely in vivo and then revert quickly in vitro. Presently, there are few therapeutic options for persistent MRSA or CA bloodstream infections. Hence, there is a critical, unmet need to understand the unique interactions of the human, pathogen and therapeutic factors driving persistence outcomes. Based on our extensive preliminary data, we believe that persistent infections caused by MRSA and CA result from a three-way interaction of the pathogen, host immune response and antimicrobial agent in vivo. We hypothesize that persistent isolates: 1) have specific epigenomes to enable persistence; 2) subvert innate immune programming and memory for immune evasion; 3) evoke non-protective or maladaptive immune responses; and 4) exploit contextual immunity as persistence reservoirs. We further posit that conventional approaches to study this clinically urgent phenomenon are insufficient to understand it. We have developed three independent but synergistic research Projects to overcome these limitations. Each Project brings proven strengths and innovative approaches to bear on Specific Aims that synergize via a systems-based approach supported by outstanding technology, bioinformatics and computational Cores. Here, we will use state-of-the-art technologies to comprehensively analyze the genetics and epigenetics of pathogens and the host immune system in context of antimicrobial therapy in laboratory studies and experimental models of infection. In turn, these data will be analyzed using powerful bioinformatics and computational methods to detect hidden patterns within large complex datasets. By understanding these factors and their interactions, new approaches to identify and treat high risk patients can be developed and applied to improve and save lives. These goals are ideally aligned with priorities of the National Institutes of Health and Centers for Disease Control & Prevention.


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: 2025 ( Subtotal = $2,326,682 )
2025	2025	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG MRL	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	3	6/11/2025	NON-COMPETING CONTINUATION	$2,326,682
2025	2024	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG MRL	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	10/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,326,682

Issue Date FY: 2024 ( Subtotal = $2,344,235 )
2024	2024	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG MRL	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	5/17/2024	NON-COMPETING CONTINUATION	$2,344,235
														Subtotal = $2,344,235

Issue Date FY: 2023 ( Subtotal = $2,304,639 )
2023	2023	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	8/10/2023	NEW	$2,304,639
														Subtotal = $2,304,639

Grand Total All Awards = $6,975,556

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Systems Epigenomics of Persistent Bloodstream Infection

Award Number: U19AI172713

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 08/10/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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