**5. Mechanisms of pathogenicity and clinical course**

CT infects both sexes; however, chlamydial infections constitute primarily a female health issue since the consequences are more damaging to the reproductive tissue in women than in men. In males, CT can infect urethra, epididymis, prostate, seminal vesicles, and testis. Usually, chlamydial infections are symptomatic, less frequent, and more easily eradicated in men than in women. Nevertheless, chlamydial infection in the male genitourinary tract might induce severe damage to seminiferous tubules, spermatogenesis, and sperm cells morphology that can result in impaired male fertility [107].

Here, we focus on chlamydial infections occurring in women. In first world countries, 3 to 5% of women younger than 30 years old will be infected by CT at any point in time [90,108]. And, in over 70% of the cases, CT infection of the female genitourinary tract is asymptomatic, spoiling the prevalence or incidence rates. Consequently, it is difficult to assess the incidence of sequelae, mainly PID, tubal obstruction, and female infertility, attributable to genital CT infection.

In women, CT is the major cause of mucopurulent cervicitis (MPC) and PID. Other manifes‐ tations of chlamydial infections are vaginitis, urethritis, salpingitis, endometritis, tubo-ovarian abscess, pelvic peritonitis, periappendicitis, and perihepatitis. The symptoms more frequently reported consist of abdominal pain, dysuria, vaginal itching, and abnormal vaginal discharge. However, the most important feature of chlamydial infection in the female genital tract is the occurrence of asymptomatic infection that remains subclinical for long periods in a high rate [109,110]. Asymptomatic ascending bacteria from the cervix may produce two groups of pathologies: (i) PID-associated complications such as chronic pelvic pain, tubal obstruction, and female infertility [111,112] and (ii) adverse pregnancy outcomes such as ectopic pregnancy, miscarriage, premature rupture of membranes, chrioamnionitis, preterm birth, stillbirths, and puerperal and neonatal infections [113–115].

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

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

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

CT infects both sexes; however, chlamydial infections constitute primarily a female health issue since the consequences are more damaging to the reproductive tissue in women than in men. In males, CT can infect urethra, epididymis, prostate, seminal vesicles, and testis. Usually, chlamydial infections are symptomatic, less frequent, and more easily eradicated in men than in women. Nevertheless, chlamydial infection in the male genitourinary tract might induce severe damage to seminiferous tubules, spermatogenesis, and sperm cells morphology that

Here, we focus on chlamydial infections occurring in women. In first world countries, 3 to 5% of women younger than 30 years old will be infected by CT at any point in time [90,108]. And, in over 70% of the cases, CT infection of the female genitourinary tract is asymptomatic, spoiling the prevalence or incidence rates. Consequently, it is difficult to assess the incidence of sequelae, mainly PID, tubal obstruction, and female infertility, attributable to genital CT

response can damage the fallopian tube and generate female infertility [65,92].

extragenital tissues.

144 Genital Infections and Infertility

infection.

and undesired consequences of infection.

can result in impaired male fertility [107].

**5. Mechanisms of pathogenicity and clinical course**

General consensus in the medical community agrees that chlamydial PID is the most common preventable cause of tubal infertility and adverse pregnancy outcome [1]. However, the lack of systematic detection of the bacteria weakens these estimations, usually performed by analysis of a reduced number of cases. Approximately 20% of women with chlamydial lower genital tract infection will develop PID, 4% chronic pelvic pain, 3% tubal infertility, and 2% adverse pregnancy outcome [107]. In developing countries, the incidence and prevalence of CT infections and their harmful consequences on female reproductive tissue are not accurately known since CT infection is not routinely screened.

There is conclusive evidence that women who have suffered PID have higher risk to develop tubal infertility. A study demonstrated that 16.5% of women with abnormal laparoscopic findings likely resulting of acute PID failed to conceive, in comparison to 2.7% in control women; 10.8% developed tubal infertility, and 9.1% went through ectopic pregnancy. There‐ fore, PID increases the probability of permanent damage on female reproductive system. CT is the most common causing agent of PID; however, a drawback of this analysis is the lack of the identification of the infectious agent underlying the PID. Several randomized controlled trials to assess the value of CT screening found it helpful to reduce the incidence of PID among infected women [116–118]. The chance to develop tubal infertility after a single episode of PID is around 10% [112]. Furthermore, each episode of PID doubled the risk of tubal damage [119] independent of whether the infection was asymptomatic or not.

One of the most serious sequelae of PID and persistent chlamydial infections is the fibrosis and scarring obstruction of the fallopian tubes that leads to tubal infertility. However, the risk of tubal infertility due to CT infections is lower than PID incidence [76]. The proportion of tubal infertility among all causes of infertility varies from 40% in first-world countries to 85% in developing countries [1]. Undiagnosed and untreated chlamydial infections usually evolve to long-term persistent infections, in which chlamydial antigens chronically stimulate the host immune system. Abnormal humoral and cell-mediated immune responses and severe inflammation have been implicated in the development of immunopathological damage of fallopian tubes. Thus, the interaction between CT and the host becomes relevant for the illness outcome. However, the exact pathologic mechanism of CT-induced tubal damage and tubal infertility has not been elucidated yet.

In addition, acute and chronic maternal chlamydial infections constitute a significant risk factor for adverse pregnancy outcomes and newborns contagion. Untreated and persistent infections are strongly associated with ectopic pregnancy, which is the tubal development of the embryo and constitute the main cause of maternal mortality in the first trimester of pregnancy in developing countries. In addition, miscarriage, chrioamnionitis, low birth weight, stillbirth, premature rupture of membranes, and preterm birth are frequent pathological consequences of chlamydial infections [51,113,114]. Several mechanisms may contribute to the development of these pathologies, including direct fetal infection, placental damage, and severe puerperal maternal illness [120–124]. Nevertheless, the exact nature of chlamydial infection pathogenesis during pregnancy remains unexplained.

CT infections can also be vertically transmitted to newborns during labor, resulting in chlamydial conjunctivitis and/or pneumonia, which may possibly involve similar pathogen‐ esis mechanisms to those occurring in the female genital tract.

Controversial reports point out CT as a risk factor for cervical carcinoma, independent of human papillomavirus [107]. It has been shown that CT interferes with multiple proapoptotic pathways to guarantee survival within host cells [125,126]. In addition, CT activates prosur‐ vival signaling pathways for bacterial nutrient acquisition, expression of antiapoptotic factors, and synthesis of proinflammatory cytokines [127,128]. On the other hand, CT interferes with chromosome segregation and cytokinesis. In consequence, multinucleated cells and cells with aberrant number of chromosomes are often observed in cell cultures infected with CT [129]. Taken together, these findings suggest that persistent chlamydial infections might play a role in the development of cervical neoplasia. Further research is needed to shed light to this issue.

The high prevalence and incidence estimates worldwide, in conjunction to the diversity of clinical entities and long-term consequences of chlamydial infections, propel further research of the bacterial and host factors involved in the pathogenesis and damage to the reproductive system.
