# Viral and immune-mediated CNS pathology during SARS-CoV-2 infection

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $417,822

## Abstract

Project Summary
The COVID-19 pandemic has rampantly affected the population of the world and created lasting effects on the
economy, health and psyche of the global community. Although it shares similarities with SARS-CoV-1, the full
extent of the pathophysiology caused by SARS-CoV-2 is unclear. In particular, extrapulmonary manifestations
effects of SARS-CoV-2 infection remain poorly understood. Case series from China and Europe suggest that
the central nervous system is involved in the disease process in at least a subset of patients, with some reports
estimating up to 30% of COVID-19 patients having neurological symptoms, including seizure, intractable
headache, and impaired smell and taste. Although there are reports of neurological disease in in COVID-19
patients, it is unclear if SARS-CoV-2 invades the central nervous system (CNS). Studies of other
coronaviruses, including SARS-CoV-1, demonstrate clear neurotropism as well as neuroinflammation
associated with other members of this family of viruses. These studies raise the possibility that SARS-CoV-2
may cause neurological symptoms either through invasion of the CNS or through an increase in inflammatory
cytokines within the CNS. We hypothesize that SARS-CoV-2 infections have neuroinvasive potential and lead
to altered and hyperinflammatory immune states within the CNS of infected individuals. We further hypothesize
that infection of the CNS exacerbates respiratory dysfunction through direct toxicity of ACE2 expressing
neurons that are critical regulators of cardiopulmonary function. Our investigations will combine the power of
human studies with those utilizing mouse models in which we can readily administer virus and assess for
pathophysiology. Aim 1, we will determine the CNS immune responses in COVID-19 patients with
neurological symptoms. Using a combination of single cell RNA-sequencing, cytokine profiling, viral
sequencing and antibody validations, we will fully dissect out the inflammatory responses within the CNS
compartment compared to the systemic circulation in COVID-19 patients. Using mouse models, in Aim 2, we
will investigate the encephalitic potential of SARS-CoV-2. Using several complementary approaches to
infect mice with SARS-CoV-2, we will introduce the virus into the central nervous system of mice. Using
depletion antibodies and various knockout mice, we will identify which immune cells are required for
neuropathology in these mice through survival studies, flow cytometry and immunofluorescent staining. Finally,
in Aim 3, we will evaluate the effects of CNS infection on respiratory outcomes. Because of the known
expression of ACE2 in the brainstem, and the brainstem’s critical role in regulating cardiopulmonary functions,
we suspect that CNS infection with SARS-CoV-2 will exacerbate SARS-CoV-2 respiratory disease.
These three aims will help support our hypotheses of how SARS-CoV-2 infections can affect the CNS and
respiratory compartments. We expect that our findings wi...

## Key facts

- **NIH application ID:** 10223167
- **Project number:** 5R01AI157488-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Shelli Farhadian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $417,822
- **Award type:** 5
- **Project period:** 2020-07-24 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223167

## Citation

> US National Institutes of Health, RePORTER application 10223167, Viral and immune-mediated CNS pathology during SARS-CoV-2 infection (5R01AI157488-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10223167. Licensed CC0.

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