# Antiviral innate immune responses to pathogenic coronaviruses in the nasal epithelium

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2024 · $15,438

## Abstract

Project Summary / Abstract
MERS-CoV (MERS) and SARS-CoV-2 (SARS-2) are highly pathogenic coronaviruses (CoVs) that have
emerged and caused public health emergencies in the past 20 years. Both of these pathogenic CoVs are
betacoronaviruses, although from different lineages (merbeco and sarbeco, respectively). Like other
respiratory viruses, CoVs enter the respiratory tract and establish an infection in the upper airway epithelium,
where they encounter host innate immune defenses. All CoVs produce double-stranded RNA (dsRNA) as a
byproduct of their replication, and this intermediate can induce three innate immune pathways in host cells:
interferon (IFN) production and signaling, the protein kinase R (PKR) pathway, and the OAS/RNase L system.
Studies of MERS in lower airway cell lines has shown that this virus is particularly adept at evading these
dsRNA-induced innate immune pathways. This contrasts with SARS-2, which activates IFN, PKR, and RNase
L pathways. Relatively little has been done to characterize the role that these pathways may play in limiting
MERS and SARS-2 infection in the upper airway. Additionally, mucosal innate immune defenses such as
antimicrobial peptides (AMPs) and nitric oxide (NO) that are highly expressed in the nasal epithelium have only
recently been recognized as antiviral, and their role during CoV infection has yet to be characterized. Similarly,
mucus production and ciliary function are primary innate immune defenses in the upper airway epithelium, and
their specific roles in limiting SARS-2 and MERS infection is unclear. Interestingly, MERS and SARS-2 have
different cellular tropisms in the nasal epithelium, with MERS predominantly infecting mucus-producing goblet
cells and SARS-2 infecting ciliated cells, suggesting innate immune responses to these viruses may differ. I
propose to use a primary nasal epithelial culture system to characterize these innate immune effector functions
in the upper airway during MERS and SARS-2 infection. I hypothesize that previously underappreciated
epithelial innate defenses such as AMP production, NO synthesis, and mucociliary mechanisms
function to limit MERS and SARS-2 replication and spread in the nasal epithelium alongside dsRNA-
induced innate immune pathways. My first aim will utilize a panel of SARS-2 and MERS recombinant viruses
expressing inactive forms of important viral innate immune antagonists to characterize activation and evasion
of dsRNA-induced innate immunity and downstream effects of activation of these pathways (cytokine
production, cell death). My second aim will elucidate the role of ciliary and mucus function during SARS-2 and
MERS infection by pharmacologically perturbing these innate processes, and will investigate the activation of
and the potential inhibitory role of epithelial AMP and NO responses during MERS and SARS-2 infection. The
experiments proposed will begin to characterize immune responses to pathogenic CoVs in the upper airway
epithelium, the prim...

## Key facts

- **NIH application ID:** 10909018
- **Project number:** 5F30AI172101-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Clayton Otter
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $15,438
- **Award type:** 5
- **Project period:** 2023-08-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909018

## Citation

> US National Institutes of Health, RePORTER application 10909018, Antiviral innate immune responses to pathogenic coronaviruses in the nasal epithelium (5F30AI172101-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10909018. Licensed CC0.

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