Sex Drives Dimorphic Immune Responses to Viral Infections

Abstract

New attention to sexual dimorphism in normal mammalian physiology and disease has uncovered a previously unappreciated breadth of mechanisms by which females and males differentially exhibit quantitative phenotypes. Thus, in addition to the established modifying effects of hormones, which prenatally and postpubertally pattern cells and tissues in a sexually dimorphic fashion, sex differences are caused by extragonadal and dosage effects of genes encoded on sex chromosomes. Sex differences in immune responses, especially during autoimmunity, have been studied predominantly within the context of sex hormone effects. More recently, immune response genes have been localized to sex chromosomes themselves or found to be regulated by sex chromosome genes. Thus, understanding how sex impacts immunity requires the elucidation of complex interactions among sex hormones, sex chromosomes, and immune response genes. In this Brief Review, we discuss current knowledge and new insights into these intricate relationships in the context of viral infections.

Figure 1

Mechanisms of tissue sexual dimorphism that underlie sex differences in immune responses. Sex hormones, such as estrogens and androgens, contribute to both organizational and activational effects via gene effects that include both promoter activation and chromatin remodeling (epigenetic modifications). Sex chromosome complement exerts its effect in promoting sexual dimorphism independent of sex hormones. X-dosage compensation and escape from X-inactivation influence differential gene expression of innate immune molecules. Y chromosome contributions include Y gene-associated polymorphisms. Studies evaluating sexual dimorphism in immune responses focus on the interdependence of these factors as well as their independent contributions.

Figure 2

The interplay of sex chromosomes, sex hormones and immune responses influence sex differences in virologic control. Females display increased innate and adaptive immune responses to most viral infections compared to males, due to difference in effects of sex hormones (estrogen, progesterone and androgen). X and Y chromosome complement also contributes to sexually dimorphic immune responses to viruses in females and males. The relative increase in immune responses in females may contribute to differential levels of virologic control during acute infections and/or immunopathologic effects of anti-viral T cells that may lead to chronic inflammation.