Sex chromosome complement and sex steroid signaling underlie sex differences in immunity to respiratory virus infection

Abstract

Epidemiological studies have revealed sex differences in the incidence and morbidity of respiratory virus infection in the human population, and often these observations are correlated with sex differences in the quality or magnitude of the immune response. Sex differences in immunity and morbidity also are observed in animal models of respiratory virus infection, suggesting differential dominance of specific immune mechanisms. Emerging research shows intrinsic sex differences in immune cell transcriptomes, epigenomes, and proteomes that may regulate human immunity when challenged by viral infection. Here, we highlight recent research into the role(s) of sex steroids and X chromosome complement in immune cells and describe how these findings provide insight into immunity during respiratory virus infection. We focus on the regulation of innate and adaptive immune cells by receptors for androgen and estrogens, as well as genes with a propensity to escape X chromosome inactivation. A deeper mechanistic knowledge of these pathways will help us to understand the often significant sex differences in immunity to endemic or pandemic respiratory pathogens such as influenza viruses, respiratory syncytial viruses and pathogenic coronaviruses.

Keywords: X chromosome inactivation; androgen; estrogen; pulmonary immunity; respiratory virus; sex differences.

FIGURE 1

The immune response to ssRNA viral infection is regulated by sex steroid receptors and gene dosage on the X chromosome. Letters indicating each cell type or pathway are defined in Table 1. Figure created with BioRender.com.

FIGURE 2

Interaction between sex steroid receptors and escape from XCI in pDCs. Signaling through ER results in increased pDC responsiveness to TLR7 signaling and TLR7-mediated IFN-I production. Additionally, ER activity increases transcription of IFNA/B and interferon-responsive genes (ISGs), both through increased production of IFN-I leading to signaling through the IFNAR, as well as increased expression of IRF5. Escape from XCI by TLR7 and CXORF21 results in biallelic transcription of the genes. Increased levels of TLR7 and TASL (the protein encoded by CXORF21) also result in increased transcription of IFNA/B and increased production of IFN-I. Figure created with BioRender.com.