Sex differences in innate anti-viral immune responses to respiratory viruses and in their clinical outcomes in a birth cohort study

Eteri Regis,Sadia Haider,Adnan Custovic,Sebastian L Johnston,Angela Simpson,Rebecca Howard,Michael R Edwards,Sara Fontanella,John A Curtin,Magnus Rattray,Lijing Lin

doi:10.1038/s41598-021-03044-x

Abstract

The mechanisms explaining excess morbidity and mortality in respiratory infections among males are poorly understood. Innate immune responses are critical in protection against respiratory virus infections. We hypothesised that innate immune responses to respiratory viruses may be deficient in males. We stimulated peripheral blood mononuclear cells from 345 participants at age 16 years in a population-based birth cohort with three live respiratory viruses (rhinoviruses A16 and A1, and respiratory syncytial virus) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2) and investigated sex differences in interferon (IFN) responses. IFN-α responses to all viruses and stimuli were 1.34–2.06-fold lower in males than females (P = 0.018 − < 0.001). IFN-β, IFN-γ and IFN-induced chemokines were also deficient in males across all stimuli/viruses. Healthcare records revealed 12.1% of males and 6.6% of females were hospitalized with respiratory infections in infancy (P = 0.017). In conclusion, impaired innate anti-viral immunity in males likely results in high male morbidity and mortality from respiratory virus infections.

Highlights

The mechanisms explaining excess morbidity and mortality in respiratory infections among males are poorly understood
We first investigated whether frequencies of early-life lower respiratory tract infections (LRTIs) differed between sexes in our cohort to ensure the study population was representative of the excess morbidity with virus infections observed in males in the general population
There was a significant difference between the sexes in the proportion of children admitted to hospital with LRTI in the first year of life, with 56/498 (11.2%) of males and 28/418 (6.7%) of females being hospitalized (P = 0.018)

Summary

Introduction

The mechanisms explaining excess morbidity and mortality in respiratory infections among males are poorly understood. Male predominance was reported in rates of hospitalization due to lower respiratory tract infections (LRTIs) of all causes in danish populations under the age of 25 y ears[9]. These profound sex differences have been highlighted by the immense global impact of COVID-1910, in which risk factors for mortality include older age, the presence of comorbid conditions, and male sex[11,12]. The association of infection rates and poor outcomes with male sex is consistent across different respiratory viruses, but the mechanisms explaining excess morbidity in males are poorly u nderstood[21]. Manchester Academic Health Sciences Centre, University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, UK. 4These authors contributed : Eteri Regis, Sara

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Conclusion