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Roles of the renin-angiotensin-aldosterone system in the innate immune response to influenza virus infection

Award Number: R16AI201117
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: 07/24/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Roles of the renin-angiotensin-aldosterone system in the innate immune response to influenza virus infection - PROJECT SUMMARY/ABSTRACT The long-term goal of this proposal is to understand how the renin-angiotensin-aldosterone system (RAAS) controls inflammation during influenza virus infection. An estimated 47 million influenza infections occur each year in the US, with 610,000 needing hospital care for associated respiratory and heart symptoms. 27,000 deaths occur each year in the US from influenza infections, and 645,000 deaths occur worldwide. One roadblock to understanding the pathogenesis of influenza infection is the relative contributions of the virus and host factors have not well characterized in vivo. Severe influenza infections can result in hyperinflammation that can progress to sepsis. One hallmark of acute respiratory distress syndrome is the activation of RAAS as elevated angiotensin II levels correlate with severity. RAAS functions as an endocrine system to regulate blood pressure but has also been shown to module immune function. Angiotensin II is the central signaling molecule of RAAS and functions through two receptors, AGTR1 and AGTR2. In models of acute lung injury, AGTR1 activation has been shown to be pro-inflammatory and AGTR2 as anti-inflammatory. Neutrophils are the most highly abundant immune cell type recruited to the lung following IAV infection, and function to exacerbate inflammation (e.g., reactive oxygen species (ROS) release), recruit additional immune cells, and/or resolve inflammation through reverse migration. More research is needed to understand how RAAS regulates neutrophil-mediated inflammation which requires the ability to monitor the response to virus infection in vivo. The zebrafish is a powerful model to study host-virus interactions as genetic tools can be combined with in vivo imaging of transparent embryos. We developed a novel zebrafish model of IAV infection where we can simultaneously monitor the movement of neutrophils and the progression of virus infection using in vivo fluorescent confocal imaging. A strength of this model is that screening small molecule drugs that improve survival following IAV infection is straightforward. We previously reported that an inhibitor of RAAS, ramipril, increased survival in IAV-infected larvae to 90% compared to 52% in DMSO-treated controls. In those studies, we modeled therapeutic rescue where we established a systemic IAV infection at 2 days post fertilization, waited 1 day for the infection to establish itself, and exposed the larvae to ramipril for 1 hour. Our specific goal in this proposal is to determine the mechanisms through which RAAS modulates inflammation during IAV infection. In the first aim, we will test the hypothesis that AGTR1 increases inflammation, and the second aim will test the hypothesis that AGTR2 decreases inflammation during infection. We will test these hypotheses by examining how ROS generation, nuclear-factor kappa B signaling, and neutrophil forward and reverse migration is altered by inhibiting angiotensin II levels and receptor function. Advancing our knowledge of the contribution of RAAS in the response to IAV may inform studies about responses to other viruses as well. Furthermore, findings from this research will inform the development of targeted diagnostics and anti-viral therapies for IAV and potentially other viruses.


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: 2026 ( Subtotal = $143,874 )
2026	2026	UNIVERSITY OF MAINE SYSTEM	5717 CORBETT HALL	ORONO	ME	04469	PENOBSCOT	USA	Allergy and Infectious Diseases Research	000	1	7/24/2026	NEW	$143,874
														Subtotal = $143,874

Grand Total All Awards = $143,874

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Roles of the renin-angiotensin-aldosterone system in the innate immune response to influenza virus infection

Award Number: R16AI201117

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: 07/24/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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