**1. Introduction**

272 Sex Steroids

Zellweger, R., M. W. Wichmann, et al. (1997). "Females in proestrus state maintain splenic

Zhang, Y., T. T. Song, et al. (1999). "Daidzein and genistein glucuronides in vitro are weakly

Zhang, Y., D. L. Wallace, et al. (2007). "In vivo kinetics of human natural killer cells: the

Zhu, J. and W. E. Paul (2010). "Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors." Immunol Rev 238(1): 247-62. Ziel, H. K. and W. D. Finkle (1975). "Increased risk of endometrial carcinoma among users of

concentrations." J Nutr 129(2): 399-405.

conjugated estrogens." N Engl J Med 293(23): 1167-70.

10.

immune functions and tolerate sepsis better than males." Crit Care Med 25(1): 106-

estrogenic and activate human natural killer cells at nutritionally relevant

effects of ageing and acute and chronic viral infection." Immunology 121(2): 258-65.

In this Chapter, we intend to review and discuss the current literature, and the state of the art related to the role that sex steroids play in the complex host-parasite relationship, particularly during *Taenia crassiceps* and *Taenia solium* cysticercosis. It is well known that sexsteroids regulate a variety of cellular and physiological functions of organisms such as growth, reproduction and differentiation. More recently the ability of sex steroids to affect the immunological response directed against pathogenic agents, and importantly the direct effect of these molecules on these organisms, have gained attention. These effects are clearly evident during various parasitic diseases including malaria, schistosomiasis, toxoplasmosis, cysticercosis, trypanosomiasis and leishmaniasis, where strong steroid hormone regulation of the immune response, has been described (Remoué et al., 2001; do Prado et al., 1998; Satoskar & Alexander, 1995; Vargas-Villavicencio et al., 2006; Libonati et al., 2006; Liesenfield et al., 2001). For instance, sex steroids play a significant role in regulating the parasite load in experimental intraperitoneal *Taenia crassiceps* cysticercosis of male and female Balbc/anN mice. Briefly, estrogens increase parasite loads and androgens decrease them (1) by acting directly on the parasite, favoring or hindering its reproduction, respectively, and (2) by biasing the hosts' immune response towards a parasite-permissive Th2 or a parasite-restrictive Th1 response. Recent experimental evidence, suggests that either steroids hormones may exert their effects directly upon the parasite, which may be able to exploit the host hormonal microenvironment for its exclusive benefit. The fact that steroids can directly influence parasites has been described in at least 17 different species of helminths and protozoan with medical and veterinary relevance. Briefly, we detail some of the most important experimental evidence about direct effects of steroid upon parasites. In fact, the hormonal microenvironment inside an immunocompetent host is so important, that experimental evidence suggests that an inadequate hormonal environment may lead to apoptosis of crucial parasite cells, as has been proposed in some parasites (e.g., retinoic acid

The Role of Sex Steroids in the Host-Parasite Interaction 275

Hormones and immune actors are prominent in H-P relationships (Klein, 2004). The comparatively sophisticated immune systems of vertebrates add complexity to H-P interactions. Mammals sense and react with their innate and acquired immunological systems to the presence of a parasite and the parasite is also sensitive and reactive to the host's immune systems effectors. Host's hormones are also involved in the modulation of the immune system's protective or pathogenic functions and also on the parasite's metabolism and reproduction (Roberts et al., 2001; Escobedo et al., 2005). Host's adrenal hormones are well known immune modulators (Tait et al., 2008), whilst sex steroids (estradiol, progesterone and testosterone) are progressively being recognized to also significantly affect the immune system's functions (Bouman et al., 2005; Verthelyi, 2001). More recently the ability of hormones to affect, the immunological response directed against

As stated above, sex steroids regulate a variety of cellular and physiological functions of organisms such as growth, reproduction and differentiation (Derijk & Berkenbosh, 1991; Grossman et al., 1991). More recently the ability of sex steroids to affect the immunological response directed against pathogenic agents has gained attention (Klein, 2004; Roberts et al., 2001; Escobedo et al., 2005). This is clearly evident during various parasitic diseases including malaria, schistosomiasis, toxoplasmosis, cysticercosis, trypanosomiasis and leishmaniasis where strong hormonal regulation of the immune response has been described (Remoue et al., 2001; do Prado et al., 1998; Satoskar & Alexander, 1995; Vargas-Villavicencio et al., 2006; Libonati et al., 2006; Liesenfield et al., 2001). In many sexually dimorphic species the determination of the sexual genotype upon conception, followed by the organism's physiological and endocrinological development, brings about numerous and complex differences between males and females. Starting in infancy, and thereafter along reproductive life, these differences are based on the production, secretion, and circulating concentrations of estrogens, progesterone and testosterone and caused mainly on the function and development of the hypothalamus-pituitary-gonad axis (HPG) (Angioni et al., 1991). The complex interaction between hormones produced by the HPG axis and other hormones, in addition to sex-independent gene products, determine the male and female

It may thus be inferred that, in addition to their effects on sexual differentiation and reproduction, sex hormones may also determine the differences between the sexes regarding their immune response to the same antigenic stimulus. These differences include sexual dimorphism of the immune response as well as dimorphism associated to infection parameters (Bouman et al., 2005; Morales-Montor et al., 2002b; Zuk & McKean, 1996). Besides their effects on sexual differentiation and reproduction, sex steroids (estradiol, progesterone and testosterone) can influence the immune system by affecting differently many of the functions of virtually all-immune cells types (Muñoz-Cruz et al., 2011). In fact, sexual hormones modulate a large variety of phenomena involved in the immune response, including thymocyte maturation and selection, cellular transit, lymphocyte proliferation, expression of class II major histocompatibility complex molecules and receptors, and cytokine production (Bebo et al., 2001; Da Silva, 1999). Furthermore, the presence of sex steroid receptors on immune cells (Muñoz-Cruz et al., 2011) indicates that one mechanism

pathogenic agents has gained attention (Roberts et al., 2001).

**2. Sexual dimorphism of the immune response** 

phenotypes (Besedovsky & del Rey, 2002).

has been shown to affect female *Litomosoides carinii* and microfilariae of *L. carinii, Brugia malayi, B. pahangi* and *Acanthocheilonema viteae*) (Zahner et al., 1989). In the same sense, *in vitro* experiments have shown that testosterone negatively affects fecundity in *Schistosoma. haematobium* adult worms (Remoué et al., 2002). Interestingly, this hormonal microenvironment also modulates the gene expression of female and male *S. mansoni* adult parasites. This finding may represent an interesting approach, because if we know that sexsteroids can specifically down-regulate genes involved in the fecundity and oviposition of *S. mansoni* and *S. haematobium*, we can propose the use of sex-steroid analogues to modulate this effect (Barrabes et al., 1979). Finally, parasites have developed diverse mechanisms of survival within the host, which facilitate the establishment of infection. These can be grouped into two types: those in which the immune response is evaded by strategies such as antigenic variation and molecular mimicry and those in which the parasite exploits some system of the host to its benefit, and thus obtains an advantage such as establishment, growth or reproduction. Thus *Naeglerai fowleria* is capable of internalizing antigen antibody complexes from their surface with the dual benefit of gaining the amino acids for their own metabolism and preventing the surface bound antibody from interfering with parasite host cell interactions (Shibayama et al., 2003). Other pathogens, including *Chlamydia trachomatis* and *Coxiella burnetii* have developed molecules that directly of interfere with antigen processing and presentation (Brodsky et al., 1999). A striking example of exploitation of host molecules is the ability of a number of parasites to use host-synthesized cytokines as indirect growth factors for the parasite. Recent experimental evidence has led us to suggest a mechanism of host exploitation by the parasite. In this system of 'trans-regulation' the parasite benefits directly from host derived hormones or growth factors, to allow rapid establishment, increased growth and reproduction.

In view of this evidence, it is clear that the endocrine system, particularly sex steroids, not only influences the course of parasitic infection by the modulation of the immune system, but can also be directly exploited by parasites. In this way host hormones, by means of genomic and non-genomic mechanisms, regulate important parasite processes such as growth, differentiation and reproduction, through a mechanism described as transregulation. This mechanism allows the parasite to accomplish a more successful infection.

Comprehension of these concepts, as well as the study of sex steroid receptors and of those that regulate the activity of various second messenger cascades in parasites opens interesting research perspectives in the complex host-parasite evolutionary relationship. Reports on nuclear receptors in parasites are extremely scarce and to date have only been described in six parasites. However as more parasite genome projects reach completion, evidence for these receptors in other parasites is likely to grow. The ability of a parasite to differentially affect a female or a male of the same species (sexual dimorphism of an infection) can be due to hormonal regulation of the immune response or direct hormonal affects on the parasite. Understanding the contribution of each of these and characterization of the parasite molecules involved may facilitate the development of drugs that counteract the effects of hormones on the immune system or the parasite.

The relationship between parasites (P), particularly helminthes, and their hosts (H) implies biochemical co-evolution and communication between their complex physiological and metabolic systems among themselves and with the environment, at all levels of biological organization. Hormones are known to regulate a variety of cellular and physiological functions of organisms such as growth, reproduction and differentiation (Verthelyi, 2001).

has been shown to affect female *Litomosoides carinii* and microfilariae of *L. carinii, Brugia malayi, B. pahangi* and *Acanthocheilonema viteae*) (Zahner et al., 1989). In the same sense, *in vitro* experiments have shown that testosterone negatively affects fecundity in *Schistosoma. haematobium* adult worms (Remoué et al., 2002). Interestingly, this hormonal microenvironment also modulates the gene expression of female and male *S. mansoni* adult parasites. This finding may represent an interesting approach, because if we know that sexsteroids can specifically down-regulate genes involved in the fecundity and oviposition of *S. mansoni* and *S. haematobium*, we can propose the use of sex-steroid analogues to modulate this effect (Barrabes et al., 1979). Finally, parasites have developed diverse mechanisms of survival within the host, which facilitate the establishment of infection. These can be grouped into two types: those in which the immune response is evaded by strategies such as antigenic variation and molecular mimicry and those in which the parasite exploits some system of the host to its benefit, and thus obtains an advantage such as establishment, growth or reproduction. Thus *Naeglerai fowleria* is capable of internalizing antigen antibody complexes from their surface with the dual benefit of gaining the amino acids for their own metabolism and preventing the surface bound antibody from interfering with parasite host cell interactions (Shibayama et al., 2003). Other pathogens, including *Chlamydia trachomatis* and *Coxiella burnetii* have developed molecules that directly of interfere with antigen processing and presentation (Brodsky et al., 1999). A striking example of exploitation of host molecules is the ability of a number of parasites to use host-synthesized cytokines as indirect growth factors for the parasite. Recent experimental evidence has led us to suggest a mechanism of host exploitation by the parasite. In this system of 'trans-regulation' the parasite benefits directly from host derived hormones or growth factors, to allow rapid

In view of this evidence, it is clear that the endocrine system, particularly sex steroids, not only influences the course of parasitic infection by the modulation of the immune system, but can also be directly exploited by parasites. In this way host hormones, by means of genomic and non-genomic mechanisms, regulate important parasite processes such as growth, differentiation and reproduction, through a mechanism described as transregulation. This mechanism allows the parasite to accomplish a more successful infection. Comprehension of these concepts, as well as the study of sex steroid receptors and of those that regulate the activity of various second messenger cascades in parasites opens interesting research perspectives in the complex host-parasite evolutionary relationship. Reports on nuclear receptors in parasites are extremely scarce and to date have only been described in six parasites. However as more parasite genome projects reach completion, evidence for these receptors in other parasites is likely to grow. The ability of a parasite to differentially affect a female or a male of the same species (sexual dimorphism of an infection) can be due to hormonal regulation of the immune response or direct hormonal affects on the parasite. Understanding the contribution of each of these and characterization of the parasite molecules involved may facilitate the development of drugs that counteract

The relationship between parasites (P), particularly helminthes, and their hosts (H) implies biochemical co-evolution and communication between their complex physiological and metabolic systems among themselves and with the environment, at all levels of biological organization. Hormones are known to regulate a variety of cellular and physiological functions of organisms such as growth, reproduction and differentiation (Verthelyi, 2001).

establishment, increased growth and reproduction.

the effects of hormones on the immune system or the parasite.

Hormones and immune actors are prominent in H-P relationships (Klein, 2004). The comparatively sophisticated immune systems of vertebrates add complexity to H-P interactions. Mammals sense and react with their innate and acquired immunological systems to the presence of a parasite and the parasite is also sensitive and reactive to the host's immune systems effectors. Host's hormones are also involved in the modulation of the immune system's protective or pathogenic functions and also on the parasite's metabolism and reproduction (Roberts et al., 2001; Escobedo et al., 2005). Host's adrenal hormones are well known immune modulators (Tait et al., 2008), whilst sex steroids (estradiol, progesterone and testosterone) are progressively being recognized to also significantly affect the immune system's functions (Bouman et al., 2005; Verthelyi, 2001). More recently the ability of hormones to affect, the immunological response directed against pathogenic agents has gained attention (Roberts et al., 2001).
