LAUSR

Historically, we have overlooked sex as a variable in infectious disease research [1, 2]. For example, while much of our knowledge comes from animal studies, many researchers routinely use only male animals [3]. One of the principal reasons for this is the argument that female animals, undergoing cyclic hormonal fluctuations, introduce additional experimental variation [4]. Sex bias is also a major challenge in clinical studies. In 1977, Food and Drug Administration (FDA) guidelines for human studies recommended that women of reproductive age be excluded from early clinical trials (e.g., Phase I) [1, 5]. While more recent efforts have resulted in greater inclusion of female subjects [5], the lasting consequence of this recommendation is that many drug regimens and therapeutic approaches are based solely on information gained from testing in male subjects [5–7]. Major adverse effects experienced by female patients underline that single-sex studies cannot predict whether and how men and women will respond differently to a drug, vaccine, or treatment [7]. It has become increasingly clear that sex broadly influences the host immune response [1, 2, 8]. Indeed, the influence of sexual dimorphism is likely underappreciated. The analysis of more than 14,000 wild-type and 40,000 mutant mice revealed that approximately 10% of qualitative and more than 50% of quantitative phenotypes are influenced by sex in wild-type mice [9]. Similarly, mutant phenotypes were impacted by sex in approximately 13% of qualitative and 17% of quantitative traits analyzed [9]. At the gene expression level, modest but significant differences exist between male and female liver, adipose, muscle, and brain tissue in mice [10]. In humans, as in experimental animal systems, what we now appreciate is that men generally exhibit greater susceptibility, prevalence, and severity of infection compared with women, which can be seen across a wide variety of pathogens, including parasitic, fungal, bacterial, and viral infections [1, 2, 11, 12]. Exceptions to this generality, however, can be found in which susceptibility or severity to infection, for example, is more pronounced in women. Importantly, what drives these differences is still poorly understood. By taking a closer look at two examples, urinary tract infection (UTI) and influenza, we can begin to appreciate some of the many factors that likely drive these differences.