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Pertussis inflammation is mediated by a balance between peptidoglycan recognition proteins-1 and -4

Award Number: R01AI167947
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Recent years have seen a re-emergence of pertussis as a major public health concern, despite successful mass vaccination programs. Critical pertussis disease causes over 150,000 deaths annually. Antibiotics are only effective if given before the onset of the characteristic cough. For these reasons, there is an urgent need for the development of new treatments. The long-term goal of our group is to develop anti-pertussis therapeutics. Our central hypothesis is that targeting tissue damage and inflammation induced by bacterial virulence factors will have a greater benefit than traditional bactericidal therapies. We have demonstrated the potential of sphingosine-1-phosphate receptor (S1PR) agonists in reducing pulmonary inflammation in mice and baboons. The objective of this work is to understand the beneficial elements of the S1PR agonist-mediated response to guide the next generation of anti- microbials. We identified two peptidoglycan recognition proteins (PGLYRP), -1, and -4 an antimicrobial protein, as differentially regulated by S1PR agonism. PGLYRPs elicit bactericidal activity through interactions with peptidoglycan (PGN). PGYLRP1 but not PGLYRP4 can stimulate inflammatory responses following PGN binding. We hypothesize that PGLYRP4 competes with PGLYRP1 to mediate inflammatory responses. Further, we propose that this is mediated by inhibition of host triggering receptor on myeloid cells 1 (TREM1). TREM-1 is an amplifier of inflammatory responses. It is upregulated following pattern recognition receptor activation and its activity amplifies inflammatory cytokine expression. TREM-1 ligands include PGLYRP1-PGN complexes. TREM-1 expression is reduced by S1PR agonism and inhibitor treated mice show reduced inflammatory pathology following B. pertussis infection. We hypothesize that TREM-1 acts as a checkpoint between beneficial bacterial control and detrimental inflammatory pathology.


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 = $424,733 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	3	2/27/2024	SUPPLEMENT FOR EXPANSION	$77,108
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	3	1/23/2024	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $424,733

Issue Date FY: 2023 ( Subtotal = $386,250 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	2	1/6/2023	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2022 ( Subtotal = $386,250 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	1/26/2022	NEW	$386,250
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	1	9/13/2022	NEW	$0
														Subtotal = $386,250

Grand Total All Awards = $1,197,233

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Pertussis inflammation is mediated by a balance between peptidoglycan recognition proteins-1 and -4

Award Number: R01AI167947

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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