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

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 phenotypes (Besedovsky & del Rey, 2002).

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

The Role of Sex Steroids in the Host-Parasite Interaction 277

differentiation of the parasite, and thus favor the establishment of infection. This represents a highly evolved host parasite relationship that places the parasite in an environment that, far from being hostile, endows it with growth factors that operate directly and positively on its growth and reproduction. This is independent of other elements such as the immune system. All of this amounts to the parasite exploiting endocrine mechanism developed by the host for its own advantage. It may thus be noted that the benefit of parasites to infect a host of a particular sex largely depends on the circulating steroid levels at the time of infection, and appears as the result of lengthy adaptive trials between host and parasite

Cestoda is the class of parasitic flatworms, commonly called tapeworms that live in the digestive tract of vertebrates as adults and often in the bodies of various animals as juveniles. There are two subclasses in class Cestoda, the Cestodaria and the Eucestoda. By far the most common and widespread are the Eucestoda, with only a few species of unusual worms in subclass Cestodaria. The cyclophyllideans are the most important to humans because they infect people and livestock. Two important tapeworms are the pork tapeworm, *Taenia solium*, and the beef tapeworms, *T. saginata* (Morales-Montor et al., 2004). Taennids, particularly *Taenia solium* (causal agent of porcine cysticercosis and human neurocysticercosis) and *Taenia crassiceps* (causal agent of murine cysticercosis) are highly evolved parasites that have developed diverse mechanisms of survival that facilitate their establishment in the hosts. Taennids can also exploit the hormonal microenvironment within the host in their favor (Escobedo et al., 2005; Locksley, 1997). Taennids have evolved structures similar to the steroid and protein hormone receptors expressed in upper vertebrates, with binding properties and terminal effects similar to the hormonal metabolites synthesized by the host (Damian, 1989; Salzet et al., 2000). In the next paragraphs, we summarize the findings on the role of sex steroids in two cestodes: *Taenia* 

*T. solium* is an ancient parasite that still threatens public health and porcine husbandry in Latin America, Africa and Asia, and is re-emerging in developed countries on account of the massive human migrations of modern times (Hoberg, 2002; DeGiorgio et al., 2005; Sorvillo et al., 2011). Cysticercosis results from the ingestion of the *T. solium* eggs by intermediate hosts (humans and pigs, principally), to then hatch in the intestines liberating motile oncospheres that penetrate the circulation and distribute in the organism. Oncospheres may establish in muscles, subcutaneous connective tissue, central nervous system, liver, and other organs of the host, where they develop into cysticerci, the larvae of *T. solium* contained within a vesicular translucent structure of about one cm in size (Sciutto et al., 2000). Once developed, many cysticerci die leaving scar tissue or nodular calcifications, while others live-on causing chronic and severe organic malfunction because of space-occupation and/or local inflammation, especially when located in the brain of the human intermediate host. Humans are also the only definitive hosts of the intestinal adult tapeworm, the stage in which the parasite is capable of sexual reproduction and of massive egg production. Pigs are nowadays the preferred intermediary host for the *T. solium*'s larval stage (i.e., cysticercus), a necessary

subjected to the same co-evolutionary process.

**4. The case of Cestodes** 

*crassiceps* and *Taenia solium*.

**4.1 Experimental** *T. solium* **Taeniosis/cysticercosis** 

by which sex steroids may exert their biological effects involves interactions with either cytoplasmic or nuclear receptors. For these hormones to have an effect on immune system cells, the presence of hormone receptors in these cells is necessary. Although steroid hormones also exert effects by non-genomic mechanisms by acting on cell surface receptors and triggering signaling cascades, it is currently accepted that the main route of biological activity occurs by means of specific nuclear receptors (NR) that function as transcription factors, and coordinate, after binding to their ligand, the expression of target genes. The following NR are mediators of these effects: estrogen receptors (ER) and androgen receptor (AR); the estrogen receptors ER- and ER-, each coded for by an individual gene, whose predominating ligand is 17β-estradiol; progesterone receptor (PR), which has variants A and B generated from the same gene by alternative splicing, and whose main ligand is progesterone. Androgen receptors (AR), coded for by a single gene and its ligands being testosterone and dehydrotestosterone (DHT). In fact, the binding between estradiol (E2) and its membrane ER activates group I and II of the metabotropic glutamate receptor (Boulware et al., 2005). It should here be mentioned that ER is able to bind to Src kinases through their highly conserved SH2 domains, which could considerably modify the effect of ERK 1/2 on the phosphorylation pattern of this transcription factor (Auricchio et al., 2008). Recently, three new putative membrane progesterone receptors (mPRs), mPRα, mPRβ, and mPRγ have been described and detected also on T lymphocytes (Dosiou et al., 2008). The mechanism of action of these membrane progesterone receptors is suggested to be through Gi-protein activation. Previous findings have also revealed unconventional non-genomic surface receptors for testosterone in rat T cells. These belong to the class of membrane receptors coupled to phospholipase C (PLC) via a pertussis toxin-sensitive G-protein. Binding of testosterone to these cell surface receptors causes a rapid increase in intracellular free Ca2+ concentration ([Ca2+]i) and an increased formation of inositol 1,4,5-triphosphate and diacylglycerol (Benten et al., 1999). Preliminary evidence indicates that in murine T cells, testosterone also induces a rapid rise in [Ca2+]i , presumably due to Ca2+ influx triggered by binding of testosterone to receptors on the outer surface of T cells.

#### **3. Sex steroids and immune response to helminthes parasites**

Sexual dimorphism (SD) in parasitic infections it is a scarcely studied biological phenomenon of considerable significance for individual health as well as for the evolution of species. Most of the poor knowledge about this topic is related to the wrong concept of the female supremacy in infectious diseases. However, there are many notable exceptions to this rule of a favorable female bias in susceptibility to infection. Particularly in the host's sexual differences to cystercosis infection, females are more likely to become infected, to carry larger parasite loads, to be more severely affected and more reticent to develop protective immunity to variable degrees that associate with their genetic backgrounds and times of infection. The importance of the interaction between the immune and endocrine systems becomes evident in particular circumstances of the lifespan of an organism, such as pregnancy, autoimmune diseases, and some time, it is also affected by infectious diseases. In all cases, the available evidence underscores the importance of sex steroids as immunoregulators (Verthelyi, 2001).

The hormonal microenvironment and in particular the balance of male and female hormones may favor survival of certain parasites under certain circumstances. Predominance of a sex-distinctive steroid may directly induce reproduction, growth or differentiation of the parasite, and thus favor the establishment of infection. This represents a highly evolved host parasite relationship that places the parasite in an environment that, far from being hostile, endows it with growth factors that operate directly and positively on its growth and reproduction. This is independent of other elements such as the immune system. All of this amounts to the parasite exploiting endocrine mechanism developed by the host for its own advantage. It may thus be noted that the benefit of parasites to infect a host of a particular sex largely depends on the circulating steroid levels at the time of infection, and appears as the result of lengthy adaptive trials between host and parasite subjected to the same co-evolutionary process.
