Human Cytomegalovirus Infection of Epithelial Cells Increases SARS-CoV-2 Superinfection by Upregulating the ACE2 Receptor

Greenwood, Edward Jd; Crozier, Thomas W. M.; Elder, Elizabeth; Schmitt, Janika; Crump, Colin M.; Wills, Mark R.; Sinclair, John; Baker, Stephen J.; Bradley, John R.; Dougan, Gordon; Hess, Christoph; Goodfellow, Ian; Gupta, Ravi; Kingston, Nathalie; Lehner, Paul J.; Lyons, Paul; Matheson, Nicholas J; Owehand, Willem H.; Saunders, Caroline; Smith, Kenneth; Summers, Charlotte; Thaventhiran, James; 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 M. S.; Rowlands, Jane; Ruffolo, Valentina; Tordesillas, Hugo; Bullman, Ben; Dunmore, Benjamin J.; Graf, Stefan Ting; Hodgson, Josh; Huang, Christopher L.‐H.; 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, Aloka; Epping, Madeline; Fawke, Stuart; Huhn, Oisín; Jackson, Sarah E.; Jarvis, Isobel; Marsden, Jimmy; Nice, Francesca; Okecha, Georgina; Omarjee, Ommar; Perera, Marianne; Richoz, Nathan; Sharma, Rahul; Turner, Lori; Bie, Eckart M. D. D. De; Bunclark, Katherine; Josipovic, Masa; Mackay, Michael; Mescia, Federica; Rossi, Sabrina; Selvan, Mayurun; Spencer, Sarah; Yong, Cissy; Ansaripour, Ali; Michael, Alice; Mwaura, Lucy; Patterson, Caroline; Polwarth, Gary; Polgarova, Petra; Stefano, Giovanni Di; 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 J.; Phelan, Isabel; Ranganath, Venkatesh-Prasad; Sambrook, Jennifer; Schon, Katherine; Stark, Hannah; Stirrups, Kathleen; Townsend, Paul; Ziegenweidt, Julie von; Walker, Neil; Webster, Jennifer

doi:10.1093/infdis/jiac452

Cited by 13 publications

(11 citation statements)

References 53 publications

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“…Recently Perera et al. showed that patients with severe COVID-19 had higher levels of CMV-specific IgG at the time of COVID-19 ( 28 ). Furthermore, they showed in an in vitro study that CMV increases the number of cells infected by SARS-CoV-2 and upregulates the SARS-CoV-2 receptor ACE2, the SARS-CoV-2 cell entry receptor.…”

Section: Discussionmentioning

confidence: 99%

Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry

Ljungman

Tridello²,

Piñana³

et al. 2023

Front. Immunol.

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IntroductionCOVID-19 has been associated with high morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients.MethodsThis study reports on 986 patients reported to the EBMT registry during the first 29 months of the pandemic.ResultsThe median age was 50.3 years (min – max; 1.0 – 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min – max; 0.0 – 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 – 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age (p<.0001), worse performance status (p<.0001), contracting COVID-19 within the first 30 days (p<.0001) or 30 – 100 days after HCT (p=.003), ongoing immunosuppression (p=.004), pre-existing lung disease (p=.003), and recipient CMV seropositivity (p=.004) had negative impact on overall survival while patients contracting COVID-19 in 2020 (p<.0001) or 2021 (p=.027) had worse overall survival than patients with COVID-19 diagnosed in 2022.DiscussionAlthough the outcome of COVID-19 has improved, patients having risk factors were still at risk for severe COVID-19 including death.

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Section: Discussionmentioning

confidence: 99%

Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry

Ljungman

Tridello²,

Piñana³

et al. 2023

Front. Immunol.

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“…For instance, CMV is known to be a significant pathogen in lung transplantation cases, causing severe pneumonia through a direct cytopathic effect [ 37 ]. CMV has also been found to upregulate the SARS-CoV-2 receptor ACE2, which facilitates viral entry into cells [ 38 ]. This finding implies that local CMV reactivation in the airways may exacerbate lung injury in COVID-19 patients.…”

Section: Methodsmentioning

confidence: 99%

Targeting CMV Reactivation to Optimize Care for Critically Ill COVID-19 Patients: A Review on the Therapeutic Potential of Antiviral Treatment

Schinas,

Moustaka,

Polyzou

et al. 2023

Viruses

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Cytomegalovirus (CMV) reactivation has been linked to adverse clinical outcomes in critically ill patients, with emerging evidence suggesting a potential connection with severe COVID-19. Mechanisms driving this association may include primary lung injury, amplification of systemic inflammation, and secondary immunosuppression. Diagnostic challenges in detecting and assessing CMV reactivation necessitate a comprehensive approach to improve accuracy and inform treatment decisions. Currently, there is limited evidence on the efficacy and safety of CMV pharmacotherapy in critically ill COVID-19 patients. Although insights from non-COVID-19 critical illness studies suggest a potential role for antiviral treatment or prophylaxis, the risks and benefits must be carefully balanced in this vulnerable patient population. Understanding the pathophysiological role of CMV in the context of COVID-19 and exploring the advantages of antiviral treatment are crucial for optimizing care in critically ill patients. This review provides a comprehensive synthesis of available evidence, emphasizing the need for additional investigation to establish the role of CMV treatment or prophylaxis in the management of severe COVID-19 and to develop a framework for future research on this topic.

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“…A potential worsening effect of HCMV-reactivation on the clinical course of patients is also described in severe SARS-CoV-2, but this did not impact on patient’s mortality ( 25 ) except in the very elderly ( 26 ). As a mechanistic link between HCMV-reactivation and a propagated SARS-CoV-2 infection, an upregulation of the ACE2-receptor in lung epithelial cells driven by HCMV is discussed ( 27 ). Furthermore, a study by Choi et al.…”

Section: Introductionmentioning

confidence: 99%

Exploring the relationship between HCMV serostatus and outcomes in COVID-19 sepsis

Ziehe,

Wolf,

Rahmel

et al. 2024

Front. Immunol.

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BackgroundSepsis, a life-threatening condition caused by the dysregulated host response to infection, is a major global health concern. Understanding the impact of viral or bacterial pathogens in sepsis is crucial for improving patient outcomes. This study aimed to investigate the human cytomegalovirus (HCMV) seropositivity as a risk factor for development of sepsis in patients with COVID-19.MethodsA multicenter observational study enrolled 95 intensive care patients with COVID-19-induced sepsis and 80 post-surgery individuals as controls. HCMV serostatus was determined using an ELISA test. Comprehensive clinical data, including demographics, comorbidities, and 30-day mortality, were collected. Statistical analyses evaluated the association between HCMV seropositivity and COVID-19 induced sepsis.ResultsThe prevalence of HCMV seropositivity did not significantly differ between COVID-19-induced sepsis patients (78%) and controls (71%, p = 0.382) in the entire cohort. However, among patients aged ≤60 years, HCMV seropositivity was significantly higher in COVID-19 sepsis patients compared to controls (86% vs 61%, respectively; p = 0.030). Nevertheless, HCMV serostatus did not affect 30-day survival.DiscussionThese findings confirm the association between HCMV seropositivity and COVID-19 sepsis in non-geriatric patients. However, the lack of an independent effect on 30-day survival can be explained by the cross-reactivity of HCMV specific CD8+ T-cells towards SARS-CoV-2 peptides, which might confer some protection to HCMV seropositive patients. The inclusion of a post-surgery control group strengthens the generalizability of the findings. Further research is needed to elucidate the underlying mechanisms of this association, explore different patient populations, and identify interventions for optimizing patient management.ConclusionThis study validates the association between HCMV seropositivity and severe COVID-19-induced sepsis in non-geriatric patients, contributing to the growing body of evidence on viral pathogens in sepsis. Although HCMV serostatus did not independently influence 30-day survival, future investigations should focus on unraveling the intricate interplay between HCMV, immune responses, and COVID-19. These insights will aid in risk stratification and the development of targeted interventions for viral sepsis.

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Human Cytomegalovirus Infection of Epithelial Cells Increases SARS-CoV-2 Superinfection by Upregulating the ACE2 Receptor

Cited by 13 publications

References 53 publications

Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry

Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry

Targeting CMV Reactivation to Optimize Care for Critically Ill COVID-19 Patients: A Review on the Therapeutic Potential of Antiviral Treatment

Exploring the relationship between HCMV serostatus and outcomes in COVID-19 sepsis

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