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NIH grant 1R16AI201117-01: Roles of the renin-angiotensin-aldosterone system in the innate immune response to influenza virus infection
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Benjamin L King. Award: $143874.
Start: 2026-07-24T00:00:00.
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.document fetched 2026-08-02 08:24