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

Abstract

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 harboring the rs368234815-ΔG 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.

Keywords: COVID-19; IFNλ2; IFNλ4; SARS-CoV-2; interferons; obesity.

Figure 1

Circulating Levels of Type I (IFNα2a, and IFNβ), Type II (IFNγ), and Type III [IFNλ1, IFNλ2 (IL28A), IFNλ3 (IL28B)] Interferons Stratified by IFNλ4 Expression and COVID-19 Severity Groups. Circulating Levels of Type I (IFNα2a, and IFNβ), Type II (IFNγ), and Type III [IFNλ1, IFNλ2 (IL28A), IFNλ3 (IL28B)] Interferons Stratified by IFNλ4 Expression and COVID-19 Severity Groups in the Sub-cohort (n=321). (A) Assessment of the expressing (TT/ΔG, and ΔG/ΔG) and non-expressing genotypes (TT/TT) of IFNλ4 effects on the concentration of Type I, Type II, and Type III Interferons. (B) WHO COVID-19 disease severity criteria association with plasma concentration of Interferons. (Ln) Natural log. Error bars represent the median and interquartile range. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.

Figure 2

Relationship between Type III IFNλ2 (IL28A), Obesity and COVID-19 Disease Severity. Relationship between Type III IFNλ2 (IL28A), Obesity and COVID-19 Disease Severity in the Sub-cohort (n=321). (A) Association of obesity status with plasma concentration of type III IFNλ2 (IL28A). (B) Levels of type III IFNλ2 (IL28A) in the non-obese. (C) Levels of type III IFNλ2 (IL28A) in the obese. Obesity defined as BMI ≥ 30 Kg/m². (NOb) non obese; (Ob) obese; (Ln) Natural log. Error bars represent the median and interquartile range. *P ≤ 0.05, **P ≤ 0.01.

Figure 3

Forest Plot of Factors Associated with COVID-19 Disease Severity in the Sub-cohort (n=321) in (A) Moderate and (B) Severe COVID-19 disease adjusted for age, sex at birth, Caucasian ethnicity, obesity (BMI ≥ 30 Kg/m²), metabolic disease, and respiratory disease. Mild COVID-19 disease was used as reference value. Data presented as the odds ratio [EXP(B)] with the 95% confidence interval for EXP(B).