Associations between Type III Interferons, Obesity and Clinical Severity of COVID-19

Dana Alalwan ^1* Alejandro Abner Garcia Leon ¹ Gurvin Saini ¹ Colette Gaillard ¹ Riya Negi ¹ Camille Heckmann ² Grace Kenny ¹ Eoin Feeney ^1,3 Aoife Cotter ^1,4 Christine Kelly ^1,4 Michael Carr ^5,6 Eoghan De Barra ^7,8 Obada Yousif ⁹ Mary Horgan ^1,4 Corinna Sadlier ¹⁰ Alan Landay ¹¹ Gabriel Gonzalez ¹² Patrick Mallon ^1,3 The All-Ireland Infectious Diseases Cohort Study ¹

• ¹ Centre for Experimental Pathogen Host Research, School of Medicine, College of Health and Agricultural Sciences, University College Dublin, Dublin, Ireland
• ² Université Côte d'Azur, Nice, Provence-Alpes-Côte d'Azur, France
• ³ Department of Infectious Diseases, St Vincent’s University Hospital, Dublin, Ireland
• ⁴ Department of Infectious Diseases, Mater Misericordiae University Hospital, Dublin, Ireland
• ⁵ National Virus Reference Laboratory, University College Dublin, Dublin, Ireland
• ⁶ International Collaboration Unit, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Hokkaidō, Japan
• ⁷ Department of Infectious Diseases, Beaumont Hospital, Dublin, Ireland
• ⁸ Royal College of Surgeons in Ireland, Dublin, County Dublin, Ireland
• ⁹ Department of Endocrinology, Wexford General Hospital, Wexford, Ireland
• ¹⁰ Department of Infectious Diseases, Cork University Hospital, Cork, Ireland
• ¹¹ Department of Internal Medicine, John Sealy School of Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas, United States
• ¹² Institute for Vaccine Research and Development, Hokkaido University, Hokkaido, Japan

Introduction:Severe COVID-19 is characterized by hyperimmune host responses contributing to airway damage and acute respiratory distress syndrome. Type III interferons (IFN), including IFN lambda 4 (IFNλ4), expressed in individuals harbouring the rs368234815-∆G allele, are implicated in host immune responses to viral infections, including SARS-CoV-2. Methods:We investigated associations between IFNλ4 expression through genotyping and COVID-19 disease severity in 853 laboratory-confirmed SARS-CoV-2 cases enrolled in the All-Ireland Infectious Diseases Cohort. Additionally, we measured plasma levels of Type I, II and III IFN using quantitative immunoassays along with IFNλ4 expression and COVID-19 disease severity in a sub-group (n=321 (37.6%)) with samples available within 10 days of symptom onset. IFNλ4 was expressed in 382 (44.8%) but expression was not significantly associated with COVID-19 disease severity. Results:Within the sub-group, we found no consistent associations between IFNλ4 expression and circulating IFNs. However, we observed significantly increased expression of IFNλ1 and IFNλ2 in severe COVID-19 (P<0.01), with IFNλ2 remaining significantly associated after adjustment for age, sex, ethnicity, and comorbidities, including obesity (BMI≥30 kg/m2) (P<0.001). Interestingly, although IFNλ2 levels were significantly higher in subjects with obesity, the association between higher IFNλ2 and COVID-19 disease severity was only observed in individuals without obesity (P<0.01). Conclusion:These data reveal an important role for IFNλ2 as an immune correlate that predicts COVID-19 disease severity, which may be masked in those with obesity.