Sexual dimorphism in bacterial infections

Abstract

Background: Sex differences are important epidemiological factors that impact in the frequency and severity of infectious diseases. A clear sexual dimorphism in bacterial infections has been reported in both humans and animal models. Nevertheless, the molecular mechanisms involved in this gender bias are just starting to be elucidated. In the present article, we aim to review the available data in the literature that report bacterial infections presenting a clear sexual dimorphism, without considering behavioral and social factors.

Main body: The sexual dimorphism in bacterial infections has been mainly attributed to the differential levels of sex hormones between males and females, as well as to genetic factors. In general, males are more susceptible to gastrointestinal and respiratory bacterial diseases and sepsis, while females are more susceptible to genitourinary tract bacterial infections. However, these incidences depend on the population evaluated, animal model and the bacterial species. Female protection against bacterial infections and the associated complications is assumed to be due to the pro-inflammatory effect of estradiol, while male susceptibility to those infections is associated with the testosterone-mediated immune suppression, probably via their specific receptors. Recent studies indicate that the protective effect of estradiol depends on the estrogen receptor subtype and the specific tissue compartment involved in the bacterial insult, suggesting that tissue-specific expression of particular sex steroid receptors contributes to the susceptibility to bacterial infections. Furthermore, this gender bias also depends on the effects of sex hormones on specific bacterial species. Finally, since a large number of genes related to immune functions are located on the X chromosome, X-linked mosaicism confers a highly polymorphic gene expression program that allows women to respond with a more expanded immune repertoire as compared with men.

Conclusion: Notwithstanding there is increasing evidence that confirms the sexual dimorphism in certain bacterial infections and the molecular mechanisms associated, further studies are required to clarify conflicting data and to determine the role of specific hormone receptors involved in the gender bias of bacterial infections, as well as their potential as therapeutic targets.

Keywords: Bacterial infection; Estradiol; Progesterone; Sex steroid hormones; Sexual dimorphism; Testosterone.

Fig. 1

Sex hormone effects in the expression of inflammatory mediators during bacterial infections. A schematic representation of the classic mechanism of action of progesterone (P4), estradiol (E2), and testosterone (T4) (for details, see the text), as well as the cross-talk with inflammatory signaling during bacterial infections is depicted. When bacterial virulence factors or pathogen-associated molecular patterns (PAMPs) are detected through host pattern recognition receptors such as Toll-like receptors (TLRs), signaling pathways are activated, allowing dissociation of the transcription factor NFκB from its inhibitor IκB, which is subsequently phosphorylated and degraded. Active NFκB is translocated into the nucleus and binds to response elements (NREs) of target genes, allowing the expression of pro-inflammatory genes. In general, P4 induces the expression of anti-inflammatory mediators and probably downregulates the expression of pro-inflammatory factors by sequestering NFκB and inhibiting its activity (indicated by a discontinued line arrow). On the other hand, during early response to infections or sepsis, E2 and T4 display a differential inflammatory effect, in which the former induces the expression of pro-inflammatory mediators by forming a complex with NFκB, and the latter promotes an anti-inflammatory effect. During late response to infections, E2 displays an anti-inflammatory response that prevents systemic damage, while T4 shows a persistent active pro-inflammatory response that triggers systemic damage (not shown). HR steroid hormone receptor, PR progesterone receptor, ER estrogen receptor, AR androgen receptor, HRE hormone response elements