**4. Pathogen-host interplay: Establishment of latent, repeat, and persistent infections and coinfections**

CT survival and replication heavily hinge on host cells. In fact, CT has evolved in relationship with human cells. However, little is known about the molecular basis of CT interaction with host epithelia and immune system. An increasing number of bacterial and host factors interplay for the establishment of chlamydial infection and determine the pathologic profile and clinical disease outcome. A simple scheme is shown in Figure 2 summarizing the main CT and host factors that jointly with environmental factors and the failure in diagnosis and treatment, lead to unsolved, latent, and long-term chlamydial infections.

Accordingly, estrogen and progesterone are important for the establishment of chlamydial infection. Furthermore, estrogen receptors have been involved in the internalization of CT [92,93]. Sex hormones affect the clinical outcome of chlamydial infections; thus, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone (P4), and prolactin (PRL) are involved not only in the establishment of chlamydial infection but also in the development of sequelae on reproductive tissue [94,95]. Additionally, oral contraceptive use was found to be a risk factor for CT infection. Several studies have attempted to elucidate the relation between the hormonal status at the time of infection and its contribution to tubal occlusion in genital chlamydial infection. Unfortunately, the role of sex steroids in infection outcome is far from being fully understood. Sex hormones have been shown to modulate immune responses and to have antioxidant effects in the female genital tract [96–98]. However, the mechanisms by which sex hormones may benefit or impair the colonization of genital

Sexual initiation at young age and a higher number of sexual partners are associated with increased risk of CT infection [99]. In a similar manner, having sex without protection favors CT contagion. This sexual behavior is also associated with higher incidence of sexually transmitted pathogens such as *Neisseria gonorrhoeae*, *Candida albicans*, *Human Immunodeficiency Virus*, among others [100–103]. Taken together, unsafe and high-risk sexual conduct is linked to impairment of women reproductive health, and particularly to tubal infertility. As it has been previously mentioned, some women have a genotypic predisposition to develop an abnormal immune response and severe inflammation following CT infection. In these women, there is a high rate of tubal obstruction and CT-related infertility, independent of sexual

In general, multiple sexual partners and unsafe intercourse increase the risk of CT recurrent infections and coinfection with other sexually transmitted pathogens. Thereby, the high chance to suffer repeat and chronic infections that target women reproductive tissue raises the

**4. Pathogen-host interplay: Establishment of latent, repeat, and persistent**

CT survival and replication heavily hinge on host cells. In fact, CT has evolved in relationship with human cells. However, little is known about the molecular basis of CT interaction with host epithelia and immune system. An increasing number of bacterial and host factors interplay for the establishment of chlamydial infection and determine the pathologic profile and clinical disease outcome. A simple scheme is shown in Figure 2 summarizing the main CT and host factors that jointly with environmental factors and the failure in diagnosis and

treatment, lead to unsolved, latent, and long-term chlamydial infections.

tissues by pathogenic microorganisms should be further investigated.

**3.3. Sexual behavior and other host factors**

behavior [84].

142 Genital Infections and Infertility

infertility-associated pathologies.

**infections and coinfections**

**Figure 2.** Bacterial and host factors involved in the development of female infertility. Bacterial factors such as CT geno‐ types and serovars, virulence factors, and pathogen burden, in conjunction with, host factors such as genetic predispo‐ sition and immune response, age and hormonal status, and sexual behavior participate in the establishment of the infection and pathology. Other elements that take part in the development of CT-related diseases are microbiome and coinfections with other sexually transmitted pathogens, environmental factors, and local prevalence, and most impor‐ tantly, the failure in diagnosis and treatment of chlamydial infections. Taken together, these factors sustain repeat and persistent chlamydial infections that damage female reproductive health.

Microbiome (microbial flora present at the genital tract) and the presence of other sexually transmitted pathogens may be important for the colonization of reproductive tissue and the establishment of chlamydial infection. The presence of lactobacilli in the vagina confers protection against the acquisition of chlamydial infection [104]. In contrast, indole-generating bacteria present in the microbiome or bacterial vaginosis allow CT to synthesize tryptophan, and consequently, to avoid the anti-chlamydial activity of IFN-γ [45,65]. Coinfections are more frequent in vaginosis and women with high-risk sexual behavior [100]. Clearly, coinfections exacerbate host immune response and inflammation; therefore, they favor scarring and sequelae on female reproductive system and increase the likelihood of tubal infertility.

The worst scenarios involve silent and latent infections that underline chronic persistent chlamydial infection and frequent re-infections [1]. Chlamydial infections may persist in the female upper genital tract for months in the absence of treatment. They are often asymptomatic or alternate quiescent stages with periods of clinical manifestations [105]. Actually, chronic chlamydial infections may be because of the reactivation of asymptomatic latently infected deep-seated cells. The presence of aberrant bacterial forms responsible for chlamydial persistence constitutes a long-time challenge to the immune system. Host immunopathological response can damage the fallopian tube and generate female infertility [65,92].

Reinfections, persistent infections, and treatment failure account for repeat infections that represent a substantial proportion of the chlamydial infections detected annually [106]. Repeat infection is not the sole determinant of severe genital tract pathology and sequelae. However, repeat infection increases the risk of developing tubal obstruction and female infertility [76].

Increasing evidence indicates that long-term persistence of viable aberrant chlamydial organisms within host cells is associated with inflammatory and autoimmune diseases in extragenital tissues.

In definitive, the pathogen-host interplay and the concurrency of exogenous factors appear to be related to CT-induced immunopathology. In spite of the substantial worldwide impact of chlamydial disease, the bacterial and host factors that result in infertility are still not clear. Current efforts are focused on discovering what CT is doing to the host cells to prevent sequelae and undesired consequences of infection.
