# Identifying host and viral correlates for coronavirus pathogenesis

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $497,886

## Abstract

Abstract
The coronavirus (CoV) spike protein is a key viral determinant responsible for receptor binding and
fusion/entry. The spike protein has also been predicted to be the major factor driving cross-species
transmission, allowing the emergence of epidemic strains like SARS- and MERS-CoV. In the first decade after
SARS-CoV emergence, changes to the epidemic spike that allowed binding to a new host receptor were
thought to underlie this zoonotic emergence. However, our work has shown that bat species already harbor
SARS-like CoVs with spike proteins capable of infecting human cells. These results argue that for a subset of
bat CoVs, receptor binding and infection of human cells is not the major barrier for emergence.
We found that despite equivalent replication in vitro, chimeric viruses containing bat CoV spikes have reduced
virulence in vivo. Mice infected with a chimeric SARS-CoV expressing the bat derived SHC014-CoV spike had
reduced weight loss and lethality compared to SARS-CoV controls. Importantly, this attenuation occurs despite
equivalent replication to SARS-CoV in the lung. The results indicate that virulence is dictated by more than
just the ability to infect host cells in vitro. Notably, we also found that the SHC014 spike chimera has reduced
infection of the large airways of the lung. These preliminary data shaped our central hypothesis that SARS-
CoV virulence is predicated on both host interactions with and viral motifs in the CoV spike protein.
Understanding the host and viral mechanisms that drive reduced airway infection may predict in vivo
pathogenesis and have critical implications for zoonotic emergence.
In this proposal, we explore the host factors and CoV spike changes that attenuate the zoonotic SHC014 spike
in vivo. In part one, we examine tropism changes finding that the zoonotic SHC014 spike has impaired upper
airway infection. We predict that this incompatibility relates to differences in host protease activity. We
subsequently define the specific host proteases that mediate this attenuation using both in vitro and in vivo
approaches. In part two, we use mouse-adaptation and structural analysis to predict spike changes
responsible for attenuation of the SHC014 spike. We subsequently generate mutant viruses and restore the
SHC014 spike or attenuate the SARS spike in vivo. Finally, we evaluate the mechanism of attenuation
focusing on spike interactions with host proteases. Together, the proposal identifies host proteases and spike
interactions that alter airway infection and dictate virulence following coronavirus infection. These findings
provide critical insights for understanding virulence as well as have important implications for emergence and
transmission of coronaviruses.

## Key facts

- **NIH application ID:** 10034189
- **Project number:** 1R01AI153602-01
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** VINEET D MENACHERY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $497,886
- **Award type:** 1
- **Project period:** 2020-06-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10034189

## Citation

> US National Institutes of Health, RePORTER application 10034189, Identifying host and viral correlates for coronavirus pathogenesis (1R01AI153602-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10034189. Licensed CC0.

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