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A novel multifunctional role of diverse substrate binding and import by the Haemophilus Sap transporter

Award Number: R01AI139519
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Nontypeable Haemophilus influenzae (NTHI) is a Gram-negative nasopharyngeal commensal microbe, and opportunistic pathogen that mediates human airway diseases such as otitis media (OM), acute sinusitis, chronic bronchitis, pneumonia, and exacerbations in patients with cystic fibrosis and chronic obstructive pulmonary diseases. Commensals must adapt to various microenvironmental cues for long-term colonization of the host. Disruption of commensal-host homeostasis however, can potentiate disease development. Pathogenesis is a multifactorial and dynamic process that begins with NTHI migration to a privileged site and culminates with bacterial growth. Growth is dependent upon multiple complex and coordinated interactions between the microbe(s), the varied microenvironments encountered, and interactions with host immune effectors. Bacterial strategies to thwart innate immune mechanisms and acquisition of essential nutrients are critical for NTHI pathogenesis. The goals of my laboratory are to advance our understanding of NTHI commensal and pathogenic behaviors, determine host microenvironmental cues that dictate these behaviors, and target mechanisms of pathogenesis for development of novel therapies to treat disease. We defined an essential role for the sensitivity to antimicrobial peptide (Sap) transporter in the ability of NTHI to counter the lethal effects of host-derived antimicrobial peptides (AMPs). This novel mechanism of AMP recognition, import and bacterial cytoplasmic degradation is essential for NTHI to counter host AMP lethality in vivo. Additional data from our laboratory support a multi-functional role(s) for Sap transport activity, including the acquisition of essential heme-iron. These data support the first description of an ABC transporter to import more than one diverse substrate. Further, evidence indicates that differential assembly of Sap transporter complex proteins dictates these unique physiological functions. We therefore hypothesize that Sap transporter permease and ATPase proteins coordinate assembly of unique complexes to drive energetic import of AMP molecules, and that this functional complex differs from that assembled for import of additional substrates (heme-iron). We propose to differentiate the AMP and heme binding sites in the periplasmic binding protein, SapA, by point mutant analysis and determine how SapA uses the binding pocket to recognize structurally diverse AMPs (Aim 1). We will define the molecular mechanisms of complex assembly, kinetics of substrate transport, and investigate a role for these processes in bacterial nutrition (Aim 2). As part of both aims we will validate the impact of differential substrate acquisition on NTHI persistence in the preclinical model of OM. These studies will provide the necessary information for future studies to assess bacterial adaptation in response to these microenvironmental cues in vivo and to design small molecule peptide inhibitors or molecules to block Sap- dependent functions essential for NTHI survival.


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: 2023 ( Subtotal = $454,821 )
2023	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	5	2/10/2023	NON-COMPETING CONTINUATION	$454,821
														Subtotal = $454,821

Issue Date FY: 2022 ( Subtotal = $467,483 )
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	4	2/11/2022	NON-COMPETING CONTINUATION	$467,483
														Subtotal = $467,483

Issue Date FY: 2021 ( Subtotal = $500,137 )
2021	2021	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	3	2/5/2021	NON-COMPETING CONTINUATION	$500,137
														Subtotal = $500,137

Issue Date FY: 2020 ( Subtotal = $434,861 )
2020	2020	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	2	1/31/2020	NON-COMPETING CONTINUATION	$434,861
														Subtotal = $434,861

Issue Date FY: 2019 ( Subtotal = $434,997 )
2019	2019	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	1	2/28/2019	NEW	$434,997
														Subtotal = $434,997

Grand Total All Awards = $2,292,299

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A novel multifunctional role of diverse substrate binding and import by the Haemophilus Sap transporter

Award Number: R01AI139519

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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