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Staphylococcus aureus and eicosanoid dysregulation as drivers of inflammation in aspirin-exacerbated respiratory disease

Award Number: R21AI171306
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/05/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Staphylococcus aureus and eicosanoid dysregulation as drivers of inflammation in aspirin-exacerbated respiratory disease - PROJECT SUMMARY Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by asthma, nasal polypo- sis, and acute respiratory reactions to known cyclooxygenase-1 inhibitors, including the commonly used non- steroidal anti-inflammatory drugs (NSAID), such as aspirin. Patients with AERD suffer a disproportional burden of the nasal polyposis and asthma: most AERD patients need repeated sinus surgeries, they tend to have a more severe asthma, and are more likely to develop upper and lower airway remodeling. There is no labora- tory diagnostic test available for AERD, often delaying its diagnosis. Polyp growth is associated with a strong type 2 pro-inflammatory state characterized by high systemic levels of prostaglandin D2 (PGD2) and leukotriene E4 (LTE4), eicosanoids derived from arachidonic acid. Cyclooxygenase-1 (COX-1) inhibition in AERD causes a multifold increase in PGD2 and LTE4, while it should instead decrease PGD2 and only minimally change LTE4 levels. This discrepancy suggests dysregulation of arachidonic acid metabolism, likely due to as yet unidenti- fied factors in AERD patients. To uncover the role of nasal polyps in AERD pathophysiology, we have studied Staphylococcus (S.) aureus as a frequent colonizer in the nasal polyp tissue of AERD patients. S. aureus exotoxins are known to activate leu- kotriene biosynthesis in neutrophils, and the bacteria have also been shown to invade mast cells in nasal polyps. In the proposed research, we will extend these observations by exploring the effects of S. aureus on arachidonic acid metabolism, including changes in AERD and non-AERD polyp tissue in response to COX-1 inhibition. Because S. aureus is a pathogen that often evades immune defenses, it is plausible that S. aureus can impact arachidonic acid metabolism to avoid the host’s antibacterial immune response. The proposed research will test whether colonization or infection of nasal polyps by S. aureus contributes to abnormal metabolism of arachidonic acid in AERD patients. Aim 1: To determine if S. aureus exotoxins increase pro-inflammatory eicosanoid PGD2 and LTE4, levels in AERD polyp tissue. Aim 2: To determine the mast cell transcriptional program upregulated in AERD and identify if it is induced by S. aureus. The proposed research will potentially yield a new paradigm of AERD pathogenesis in which S. aureus acts as a major environmental factor that dysregulates eicosanoid metabolism and contributes to AERD. In addition, understanding this mechanism may lead to the development of novel diagnostic markers and of therapeutic strategies to target S. aureus or mast cells to limit the extent of type-2 inflammation and improve health


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 = $201,587 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	2	5/28/2025	NON-COMPETING CONTINUATION	$201,587
														Subtotal = $201,587

Issue Date FY: 2024 ( Subtotal = $241,937 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	001	1	9/11/2024	NEW	$24,193
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	1	7/5/2024	NEW	$217,744
														Subtotal = $241,937

Grand Total All Awards = $443,524

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Staphylococcus aureus and eicosanoid dysregulation as drivers of inflammation in aspirin-exacerbated respiratory disease

Award Number: R21AI171306

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/05/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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