Associations between type III interferons, obesity and clinical severity of COVID-19

TL;DR

This study explores how type III interferons, obesity, and the severity of COVID-19 are connected, finding that IFNλ2 is linked to disease severity in non-obese individuals.

Contribution

The study identifies IFNλ2 as a potential immune marker for predicting severe COVID-19, particularly in non-obese individuals.

Findings

IFNλ2 expression is significantly associated with severe COVID-19 after adjusting for age, sex, ethnicity, and comorbidities.

Higher IFNλ2 levels are linked to severe disease only in individuals without obesity.

IFNλ4 expression was not significantly associated with disease severity.

Abstract

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 harboring the rs368234815-ΔG allele, are implicated in host immune responses to viral infections, including SARS-CoV-2.

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.

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).

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.

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