The X chromosome and sex-specific effects in infectious disease susceptibility

Abstract

The X chromosome and X-linked variants have largely been ignored in genome-wide and candidate association studies of infectious diseases due to the complexity of statistical analysis of the X chromosome. This exclusion is significant, since the X chromosome contains a high density of immune-related genes and regulatory elements that are extensively involved in both the innate and adaptive immune responses. Many diseases present with a clear sex bias, and apart from the influence of sex hormones and socioeconomic and behavioural factors, the X chromosome, X-linked genes and X chromosome inactivation mechanisms contribute to this difference. Females are functional mosaics for X-linked genes due to X chromosome inactivation and this, combined with other X chromosome inactivation mechanisms such as genes that escape silencing and skewed inactivation, could contribute to an immunological advantage for females in many infections. In this review, we discuss the involvement of the X chromosome and X inactivation in immunity and address its role in sexual dimorphism of infectious diseases using tuberculosis susceptibility as an example, in which male sex bias is clear, yet not fully explored.

Sex- and Gender-specific Observations and Implications for COVID-19

“…6 In addition, the X chromosome carries the largest number of immune-related genes in the human genome, perhaps also contributing to female's superior immune response (as well as a female preponderance in autoimmune diseases). 7 Angiotensin-converting enzyme 2 (ACE2) and its role in viral transmission and associated morbidity has also been a topic of recent COVID-19 associated discussion. ACE2 receptors on pulmonary endothelium serve as a main entry point for coronavirus.…”

COVID-19 pandemic: is a gender-defined dosage effect responsible for the high mortality rate among males?

“…SARS-Cov-1, for instance, may induce a cytokine storm (Tang et al 2016), and the viral activation of neutrophils in the case of asthma may result in lung pathology (Li et al 2013). One of the two female sex chromosomes is generally inactivated in females (Lyon 1992;Schurz et al 2019). In female immune cells, however, TLR7 genesand probably TLR8escape such silencing.…”

Neonatal melioidosis case reports—Lessons learned

“…Association of the male sex with fatal neonatal melioidosis although was not statistically significant ( P = .2127), there could be an underlying biological significance given the consistently reported higher incidence in male across the age groups. Other infectious diseases that demonstrate higher incidence in male include syphilis, tuberculosis, influenza, hepatitis, and leishmaniasis . Future study is needed to determine if there were sex‐specific biological factors that affect human immune response and susceptibility to B pseudomallei infection as the epidemiological evidences appear to implicate.…”

“…Other infectious diseases that demonstrate higher incidence in male include syphilis, tuberculosis, influenza, hepatitis, and leishmaniasis. 23 Future study is needed to determine if there were sex-specific biological factors that affect human immune response and susceptibility to B pseudomallei infection as the epidemiological evidences appear to implicate. A neglect of study in this area could potentially cause opportunity to be missed for the development of improved melioidosis treatment methods that take into account patients' sex-specific biological factors.…”