Airway Epithelial-Myeloid cell crosstalk as a key mechanism in the pathogenesis of Coronaviruses

Human coronaviruses (hCOV) are important pathogens. Less pathogenic hCoVs - e.g. hCoV-229E are a broad group of CoVs that infect humans but cause only a mild 'common-cold-like' disease, whereas two highly pathogenic hCoVs: severe acute respiratory syndrome (SARS)-CoV-1 and MERS-CoV have become a threat to human health. In 2018, the World Health Organization (WHO) designated MERS-CoV and SARS-CoV-1 as 'Blueprint Priority Diseases',
meaning there is an urgent need to develop vaccines and better understanding of how CoVs establish infection in susceptible hosts.
SARS-CoV-2 recently emerged and has subsequently become pandemic, with significant effects on the health and socioeconomic outlook of almost all nations. SARS-CoV-2 causes mild to severe respiratory illness, named COVID-19, which is exacerbated by aging and comorbidities. Some patients can develop acute respiratory distress syndrome (ARDS) or multi-organ injuries, associated with elevated levels of pro-inflammatory cytokines, including IL-6 and TNF-a, alongside minimal amounts of type I IFNs. Reduced Type I IFN production is likely caused by viral antagonism of innate immune responses hampering induction of a robust anti-viral state in the airway epithelium and surrounding tissues and facilitating increased SARS-CoV-2 titres.
We hypothesise that crosstalk between infected lung epithelial cells, targeted by SARS-CoV-2 but poor cytokine producers, and myeloid cells, not susceptible to SARS-CoV-2 infection but major producers of cytokines, will contribute to the cytokine imbalance and storm characteristic of COVID19.
The main objective of this study is to establish the role of monocytes/macrophages as amplifiers of inflammatory responses during SARS-CoV-2 infection including evaluating the differential effect(s) of: SARS-CoV-2 variants, existing or new drugs and donor characteristics. We will also compare SARSCoV-2 to different coronaviruses to provide additional insight into the pathogenesis of hCoV infections more generally.
Key stages for the project:
1. Creation and use of primary human airway epithelial cultures to model SARS-CoV-2 pathogenesis. Using our combined expertise, we will extend our initial human cell models to study
virus:host interactions in the airway.
2. Investigate if and how the presence of human macrophages influences SARS-CoV-2 infection of differentiated human lung epithelial cells.
3. Characterise the capacity of different SARS-CoV-2 variants e.g. Alpha, Delta, Omicron to initiate responses in the model.
Based on progress we will extend the study to:
4. Characterise the capacity of different coronaviruses including SARS-CoV-1, MERS-CoV and less pathogenic hCoVs to initiate responses in the in vitro model.
5. Determine the effects of existing e.g. dexamethasone and more novel drugs on 1-4.
6. Investigate the impact of donor characteristics e.g. age, ancestry on 1-4.
Main readouts will include: hCoV replication, cytotoxicity, cytokine production and changes in global gene expression signature in both airway epithelial and macrophage cell types (RNA-seq).
This project has the potential to identify novel targets for anti-coronavirus therapeutics for use in current and future outbreaks. This proposal combines the expertise of investigators across schools and disciplines including airway
epithelial cell models/respiratory medicine (Prof. Sayers), macrophages/immunology (Dr MartinezPomares) and coronaviruses (Dr Coleman).