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Mechanisms of peptidoglycan-induced modulation of metabolic and inflammatory responses to bacteria

Award Number: R01AI148465
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 Immune surveillance by phagocytic cells plays a vital role in controlling infections by internalize bacteria and kill them by a process of enzymatic degradation. Degradation also releases bacterial molecules that activate innate immune receptors and antigens for presentation to the adaptive immune system ultimately orchestrating the overall immune response to a microbe. The cell wall of gram-positive bacteria, like Staphylococcus aureus, is predominantly composed peptidoglycan, an amino acid-crosslinked sugar polymer. We recently demonstrated that the monomeric sugar, n-acetylglucosamine, released during peptidoglycan degradation, is inflammatory. N-acetylglucosamine interacts with the glycolytic enzyme hexokinase, inhibiting its function. As a consequence, hexokinase’s interaction with the mitochondrial outer membrane is disrupted and this dissociation initiates a signaling cascade responsible for assembly of the multi-protein NLRP3 inflammasome complex necessary for activation of the protease caspase-1. Caspase- 1 is responsible for the cleavage and activation of several key inflammatory cytokines, including IL-1b and IL-18, important for inflammatory cell recruitment and activation. Our results suggest that phagocytic cells have adapted their normal glycolytic regulation to sense abnormally high levels of a bacterial sugar as danger. To evade immune surveillance, bacteria modify their peptidoglycan layer to resist degradation by phagocytic cells and limiting the availability of innate inflammatory signals, including n-acetylglucosamine. The amount of n-acetylglucosamine impacting hexokinase function and glycolysis will depend on transport across the phagosomal membrane into the cytosol. Preliminary evidence suggests that the amount of IL- 1b produced by phagocytic cells, specifically in response to peptidoglycan, is dependent on the function of the GLUT family of sugar transports. In addition, we have generated a mouse model deficient for one of the three hexokinases expressed by phagocytic cells and observed differential impacts on glycolysis and inflammatory responses. This proposal aims to define the roles of the three hexokinases expressed by phagocytic cell in the inflammatory response to gram-positive bacteria peptidoglycan, as well characterize the transport and impact of peptidoglycan-derived n-acetylglucosamine on the metabolism and inflammatory responses of phagocytic cells. We hypothesize that the overall degree of inflammation induced by gram-positive bacteria is impacted by the amount and availability of n-acetylglucosamine generating during bacterial peptidoglycan degradation due in part to n-acetylglucosamine’s inhibition of glycolytic metabolism.


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 = $375,750 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	5	2/22/2024	NON-COMPETING CONTINUATION	$375,750
														Subtotal = $375,750

Issue Date FY: 2023 ( Subtotal = $417,500 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	2/16/2023	NON-COMPETING CONTINUATION	$417,500
														Subtotal = $417,500

Issue Date FY: 2022 ( Subtotal = $417,500 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	2/16/2022	NON-COMPETING CONTINUATION	$417,500
														Subtotal = $417,500

Issue Date FY: 2021 ( Subtotal = $417,500 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	2/19/2021	NON-COMPETING CONTINUATION	$417,500
														Subtotal = $417,500

Issue Date FY: 2020 ( Subtotal = $417,500 )
2020	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	3/9/2020	NEW	$417,500
														Subtotal = $417,500

Grand Total All Awards = $2,045,750

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Mechanisms of peptidoglycan-induced modulation of metabolic and inflammatory responses to bacteria

Award Number: R01AI148465

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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