Decoding the mild pathobiology of common cold coronaviruses to identify targets of pan-coronavirus antiviral strategies

The impact of coronaviruses (CoVs) like SARS-CoV, MERS-CoV, and SARS-CoV-2 (causing COVID-19) extends beyond 6.5 million deaths globally and significant financial strain, profoundly affecting our health system and society. Despite widespread vaccination efforts, the ongoing waves of the COVID-19 pandemic have made SARS-CoV-2 a persistent health threat. Alongside these well-known coronaviruses, common cold coronaviruses (NL63, 229E, OC43, and HKU1) are often overlooked, but can cause mild infections in healthy individuals, usually during winter. However, those with weakened immune systems may face more severe symptoms, collectively contributing to a relatively neglected public health burden. In addition, the continuous emergence of new SARS-CoV-2 variants, necessitating vaccine adjustments, poses an ongoing challenge, particularly for resource-constrained countries. These challenges underscore the urgent need for effective antiviral drugs against a range of coronaviruses. We propose that by studying how the common cold coronaviruses interact with specific cells of the airways and cause mild illnesses, we can gain valuable broader insights into coronavirus lifecycles. Effective study of these viruses faces many challenges. Primarily, we don't have enough detailed information about how they interact and enter different types of cells in our airways. The methods we currently use to study these viruses are not very reliable, and it's especially challenging to study HKU1 in a lab setting. An important question is why common cold coronaviruses prefer certain areas, cell types, and temperatures in the respiratory system. We want to understand why these viruses mainly stick to the upper respiratory tract, interacting with cells in the nose and throat and typically avoid lung infections. Additionally, we would like to investigate how temperature affects specific airway cells, which could help us disrupt virus growth and understand the seasonal patterns of these and other respiratory viruses. It's possible that lower temperatures make it easier for viruses to replicate, and exposure to cold environments might weaken the immune response, making us more susceptible to infections. The study involves infecting three-dimensional airway cells, that mimic different parts of our respiratory tract, with the common cold coronaviruses. We will use advanced techniques like single-cell RNA-sequencing to read the unique genetic code of individual cell types of the airways and how it changes during virus infection and at varying temperatures. Using receptor/factor fishing methods, similar to catching specific molecules in our cells, we will explore their interaction with viruses. We will decode the interactions of tiny sugars on our cells with these viruses through glycomics, and investigate virus-protein interactions using chemoproteomics. To make sense of all this information, we will use mathematical modelling, employing equations and computer simulations. Our ultimate goal is to see if focusing on specific cells and genes can slow down or stop infections by different coronaviruses, including new SARS-CoV-2 variants. Looking ahead, this research holds broad applications and benefits, creating new tools and systems for studying common cold coronaviruses, with a particular focus on HKU1. These advancements will facilitate in-depth research, providing valuable resources for virologists and respiratory disease experts. The detailed insights into the molecular mechanisms of common cold coronaviruses, will play a vital role in the pharmaceutical and biotechnology industries' pursuit of identifying pan-coronavirus targets for antiviral therapies. Additionally, the research includes extensive training in virology and bioinformatics for one researcher, supported by an outreach program, contributing to the broader dissemination of knowledge in these critical fields.