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Airway Epithelial-Myeloid cell crosstalk as a key mechanism in the pathogenesis of COVID-19

Reference	BB/V01854X/1
Principal Investigator / Supervisor	Professor Ian Sayers
Co-Investigators / Co-Supervisors	Dr Christopher Coleman, Dr Luisa Martinez-Pomares, Professor Dominick Shaw
Institution	University of Nottingham
Department	School of Medicine
Funding type	Research
Value (£)	247,808
Status	Completed
Type	Research Grant
Start date	05/01/2021
End date	04/07/2022
Duration	18 months

Abstract

unavailable

Summary

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2, the cause of COVID-19, causes mild to severe respiratory illness exacerbated by aging and comorbidities. 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-alpha, 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 facilitating increased viral 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 COVID-19. 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 effect of existing or new drugs. Towards this aim we will (1) Characterise SARS-CoV-2 infection in differentiated primary human airway epithelial cells, both nasal and bronchial cells including; viral growth, cytotoxicity and cytokine production. (2) Determine if crosstalk between airway epithelial cells and monocytes/macrophages influences SARS-CoV-2 infection and can be targeted by existing and new drugs. We will use individual and co-cultures of airway epithelial cells and monocytes/macrophage to (i) investigate changes in cytokine production, (ii) determine if SARS-CoV-2 infection of epithelial cells can be augmented by the presence of myeloid cells, (iii) if monocytes/macrophages can become targets for SARS-CoV-2 and (iv) the effect of drugs on each aspect.

Committee	Not funded via Committee
Research Topics	Immunology, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	Covid19 Rapid Response [2020]
Funding Scheme	X – not Funded via a specific Funding Scheme

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