# Brain pathophysiology in SARS-CoV-2 disease

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2022 · $630,502

## Abstract

SARS-CoV-2, the virus underlying the current COVID-19 pandemic, not only affects peripheral tissues, it also
targets the brain causing microvascular lesions, microhemorrhages and neurological manifestations. The
internalization of SARS-CoV-2 is initiated by the binding of the virus spike protein to angiotensin converting
enzyme 2 (ACE2) on the membrane of host cells including endothelial cells throughout cerebral capillaries.
ACE2 is internalized along with the virus thereby leading to a state of ACE2 deficiency. ACE2 is a critical member
of the renin-angiotensin system (RAS). This enzyme catabolizes the octapeptide hormone angiotensin-[1-8]
thereby protecting cells and tissues from the vasoconstrictor, pro-inflammatory and pro-thrombotic effects of
overactive angiotensin type 1 receptors (AT1Rs). Blocking AT1Rs with an AT1R antagonist protects mice from
behavioral impairments due to ACE2 deficiency. Lipopolysaccharide (LPS) causes microglia activation and
neuronal cell loss and is widely used as an experimental model of neuroinflammation. The brain pathophysiology
induced by LPS shares many similarities with SARS-CoV-2 infection. We hypothesize that under conditions of
reduced ACE2 (i.e., ACE2 knockout mice or SARS-CoV-2-infected hamsters), AT1R activity is upregulated in
the microvasculature. In the presence of an inflammatory insult (i.e., LPS or SARS-CoV-2), AT1Rs promote
endothelial dysfunction in the microvasculature through pro-inflammatory and pro-thrombotic signaling pathways
leading to blood brain barrier injury. Deficits in cognition and increased anxiety ensue. We will test this overall
hypothesis through the following specific aims: Determine the mechanisms of the pro-injury (Aim 1) and
protective (Aim 2) arms of the RAS that regulate the pathophysiology of the brain in animal models of
neuroinflammation and COVID-19. (Aim 3) Determine the mechanisms underlying the effects of biological sex
and age in the brain pathophysiology induced by LPS and SARS-CoV-2. Studying RAS mechanisms in the brain
will provide insight into on-going and future clinical trials of therapeutics for treating brain injury associated with
COVID-19 and other diseases of neuroinflammation. In addition, focusing on mechanisms underlying the effects
of biological sex and age on microvasculature pathophysiology in models of neuroinflammation and COVID-19
will shed light into why male sex and age are major risk factors for COVID-19 severity.

## Key facts

- **NIH application ID:** 10434951
- **Project number:** 5R01NS124204-02
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** JUAN M SAAVEDRA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $630,502
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434951

## Citation

> US National Institutes of Health, RePORTER application 10434951, Brain pathophysiology in SARS-CoV-2 disease (5R01NS124204-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10434951. Licensed CC0.

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