Role of sex steroid hormones in bacterial-host interactions

Abstract

Sex steroid hormones play important physiological roles in reproductive and nonreproductive tissues, including immune cells. These hormones exert their functions by binding to either specific intracellular receptors that act as ligand-dependent transcription factors or membrane receptors that stimulate several signal transduction pathways. The elevated susceptibility of males to bacterial infections can be related to the usually lower immune responses presented in males as compared to females. This dimorphic sex difference is mainly due to the differential modulation of the immune system by sex steroid hormones through the control of proinflammatory and anti-inflammatory cytokines expression, as well as Toll-like receptors (TLRs) expression and antibody production. Besides, sex hormones can also affect the metabolism, growth, or virulence of pathogenic bacteria. In turn, pathogenic, microbiota, and environmental bacteria are able to metabolize and degrade steroid hormones and their related compounds. All these data suggest that sex steroid hormones play a key role in the modulation of bacterial-host interactions.

Figure 1

Mechanisms of action of sex steroid hormones. (a) Schematic representation of the main functional domains of sex steroid intracellular receptors. Transactivation domain (A/B) contains a transcriptional activation function (AF1). The C domain contains the DNA-binding domain (DBD) and a dimerization interface (DI). The hinge region (D domain) contains the nuclear localization signal (NLS) and binding sites for chaperones (Hsp). The ligand-binding domain (LBD) is contained in the E domain, which also contains part of AF-2 region and a site for coregulators association. The F domain includes part of AF-2. Domains are not represented to scale, modified from [10]. (b) Classical and nonclassical mechanisms of action of sex steroid hormones. Through the classical mechanism, sex hormones (SHs) exert their function by binding to specific intracellular receptors (R). In the absence of ligand, receptors are associated with heat-shock proteins (Hsps); when the hormone interacts with its specific intracellular receptor, it induces conformational changes that allow the dissociation of Hsp, promoting dimerization, phosphorylation, and receptor binding to hormone response elements located in the promoter region of target genes. Then, receptors act as ligand-dependent transcription factors, recruit coregulators, and associate to the basal transcription machinery. Alternatively, through a nonclassical mechanism, sex hormones bind to membrane receptors (mRs) that in many cases are coupled to G proteins, which stimulate several signal transduction pathways, for example, through kinase activation, modified from [11].

Figure 2

Effects of sex steroid hormones on bacterial infections. In general, male mammals are more susceptible to bacterial infections and its negative outcomes than their female counterparts. This is due to the suppressor effect of testosterone on the immune system, while estradiol acts as an activator of the immune system. Testosterone reduces the NK cell activity and induces the production of anti-inflammatory cytokines such as IL-10, whereas it reduces the production of proinflammatory cytokines such as TNFα through the inhibition of NFκB. This conduces to an inappropriate proinflammatory response that in turn allows the progression of the infection and its negative effects, such as an increase in mortality. In some cases, the limited proinflammatory response leads to a latent infection that can be abated and conduces to recovery. Progesterone acts as a modulator of the immune system due to its suppressing effects by reducing the NK cell activity, inducing the production of IL-4, IL-5 and IL-10 and increasing the expression of SOCS1, while inhibiting the production of IFNγ and TNFα, which avoid the development of bacterial infections, subsequent bacteremia, and sepsis. However, in high levels, for example during pregnancy, progesterone predisposes to some bacterial infections due to reduced proinflammatory responses. On the other hand, estradiol enhances the NK cell activity, and through the activation of NFκB, induces the production TNFα, IL-1, IL-6. IL-17, and IL-23, while inhibiting the production of IL-4, IL-10, IL-12, and TGF-β, and allows the bacterial clearance and recovery from infection. However, estradiol can also produce an excessive proinflammatory response and increased mortality as a consequence of susceptibility to infection and multiple organ failure. +, increase; −, reduction.