Human Cytomegalovirus Infection of Epithelial Cells Increases SARS-CoV-2 Superinfection by Upregulating the ACE2 Receptor
Authors: Perera Marianne R , Greenwood Edward J D , Crozier Thomas W M , Elder Elizabeth G , Schmitt Janika , Crump Colin M , Lehner Paul J , Wills Mark R , Sinclair John H ,   the Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research COVID BioResource Collaboration, Baker Stephen , Bradley John , Dougan Gordon , Hess Christoph , Goodfellow Ian , Gupta Ravi , Kingston Nathalie , Lehner Paul J , Lyons Paul A , Matheson Nicholas J , Owehand Willem H , Saunders Caroline , Smith Kenneth G C , Summers Charlotte , Thaventhiran James E D , Toshner Mark , Weekes Michael P , Bucke Ashlea , Calder Jo , Canna Laura , Domingo Jason , Elmer Anne , Fuller Stewart , Harris Julie , Hewitt Sarah , Kennet Jane , Jose Sherly , Kourampa Jenny , Meadows Anne , O’Brien Criona , Price Jane , Publico Cherry , Rastall Rebecca , Ribeiro Carla , Rowlands Jane , Ruffolo Valentina , Tordesillas Hugo , Bullman Ben , Dunmore Benjamin J , Fawke Stuart , Gräf Stefan , Hodgson Josh , Huang Christopher , Hunter Kelvin , Jones Emma , Legchenko Ekaterina , Matara Cecilia , Martin Jennifer , O’Donnell Ciara , Pointon Linda , Pond Nicole , Shih Joy , Sutcliffe Rachel , Tilly Tobias , Treacy Carmen , Tong Zhen , Wood Jennifer , Wylot Marta , Bergamaschi Laura , Betancourt Ariana , Bower Georgie , De Sa Aloka , Epping Madeline , Fawke Stuart , Huhn Oisin , Jackson Sarah , Jarvis Isobel , Marsden Jimmy , Nice Francesca , Okecha Georgina , Omarjee Ommar , Perera Marianne , Richoz Nathan , Sharma Rahul , Turner Lori , De Bie Eckart M D D , Bunclark Katherine , Josipovic Masa , Mackay Michael , Mescia Federica , Michael Alice , Rossi Sabrina , Selvan Mayurun , Spencer Sarah , Yong Cissy , Ansaripour Ali , Michael Alice , Mwaura Lucy , Patterson Caroline , Polwarth Gary , Polgarova Petra , di Stefano Giovanni , Allison John , Biggs Heather , Butcher Helen , Caputo Daniela , Chandler Matt , Chinnery Patrick F , Clapham-Riley Debbie , Dean Anne-Maree , Dewhurst Eleanor , Fernandez Christian , Furlong Anita , George Anne , Graves Barbara , Gray Jennifer , Hein Sabine , Ivers Tasmin , Kasanicki Mary , Gresley Emma Le , Linger Rachel , Meloy Sarah , Moulton Alexei , Muldoon Francesca , Ovington Nigel , Papadia Sofia , Paraschiv Roxana , Penkett Christopher , Phelan Isabel , Ranganath Venkatesh , Sambrook Jennifer , Schon Katherine , Stark Hannah , Stirrups Kathleen E , Townsend Paul , von Ziegenweidt Julie , Walker Neil , Webster Jennifer 
Published: November 2022

Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has caused widespread morbidity and mortality since its onset in late 2019. Here, we demonstrate that prior infection with human cytomegalovirus (HCMV) substantially increases infection with SARS-CoV-2 in vitro. HCMV is a common herpesvirus carried by 40%–100% of the population, which can reactivate in the lung under inflammatory conditions, such as those resulting from SARS-CoV-2 infection. We show in both endothelial and epithelial cell types that HCMV infection upregulates ACE2, the SARS-CoV-2 cell entry receptor. These observations suggest that HCMV reactivation events in the lung of healthy HCMV carriers could exacerbate SARS-CoV-2 infection and subsequent COVID-19 symptoms. This effect could contribute to the disparity of disease severity seen in ethnic minorities and those with lower socioeconomic status, due to their higher CMV seroprevalence. Our results warrant further clinical investigation as to whether HCMV infection influences the pathogenesis of SARS-CoV-2.