REVIEW nature publishing group Chlamydia trachomatis infection: host immune responses and potential vaccines L H a f n e r 1 , K B e a g l e y 2 a n d P T i m m s 2 Chlamydia trachomatis causes genital tract infections that affect men, women, and children on a global scale. This review focuses on innate and adaptive immune responses in the female reproductive tract (FRT) to genital tract infections with C. trachomatis. It covers C. trachomatis infections and highlights our current knowledge of genital tract infections, serovar distribution, infectious load, and clinical manifestations of these infections in women. The unique features of the immune system of the FRT will be discussed and will include a review of our current knowledge of innate and adaptive immunity to chlamydial infections at this mucosal site. The use of animal models to study the pathogenesis of, and immunity to, Chlamydia infection of the female genital tract will also be discussed and a review of recent immunization and challenge experiments in the murine model of chlamydial FRT infection will be presented. CHLAMYDIAL GENITAL TRACT INFECTIONS cases of genital Chlamydia trachomatis infections reported3 Epidemiology with 496.5 cases per 100,000 population in women and 150 Sexually transmitted diseases (STDs) are a major global cause cases per 100,000 population in men. Even so, most of acute illness, infertility, long-term disability, and death, with Chlamydia cases go undiagnosed with approximately severe medical and psychological consequences for millions of 70 % of chlamydial endocervical infections in women and men, women, and children. The World Health Organization 50 % of chlamydial urethral infections in men being (WHO) states that “ in developing countries, STDs and their com- asymptomatic.4,5 It is estimated that there are plications are amongst the top five disease categories for which approximately 2.8 million new cases of Chlamydia in the adults seek health care. In women of childbearing age, STDs United States each year.6 In addition to gender, age and race are (excluding HIV) are second only to maternal factors as causes of risk factors for genital chlamydial infections. Among disease, death and healthy life lost. ” The presence of an untreated women, the highest age-specific rates were among the 15- to STD can also “ increase the risk of both acquisition and transmis- 19-year-olds (2,796.6 cases per 100,000 females) and 20- to sion of HIV by a factor of up to 10. ”1 Untreated infection with 24-year-olds (2,691.1 cases per 100,000 females). The rate of C. trachomatis is also associated with productivity losses forming Chlamydia among blacks was over eight times higher than that a substantial portion of the economic burden of disease.2 of whites (1,247 and 152.1 cases per 100,000, respectively).3 As of July 2007, the most recent international estimates are that 340 million new cases of STD infections occurred worldwide in C. trachomatis infection 1999 of which around 92 million were chlamydial infections In vivo , the intracellular, biphasic developmental cycle of the affecting more women (50 million) than men. The prevalence Gram-negative bacterium C. trachomatis is reliant on host cell of Chlamydia in adults (persons between 15 and 49 years of ATP and nutrients for its existence. In this unique cycle, the age) also varies across the world and is highest for females bacterium is normally found in two highly specialized (24 million) and males (19 million) in South-East Asia followed morphologic forms — the extracellular, metabolically inactive, by adults (15.8 million) in sub-Saharan Africa. The highest rate and infectious elementary body (EB) and the metabolically (119) of new cases of infected adults per 1,000 population has active, intracellular form known as the reticulate body (RB) occurred in sub-Saharan Africa. 1 that divides by binary fission within the inclusion (reviewed Chlamydia remains the most commonly reported infec- in ref. 7). The infectious EB enters the mucosal host cells in tious disease in the United States. In 2005, there were 976,445 a process now known to be independent of host cell-surface 1 Department of Life Sciences, Queensland University of Technology, Brisbane , Queensland, Australia . 2 Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane , Queensland , Australia . Correspondence: L Hafner ([email protected]) Received 8 July 2007; accepted 6 December 2007; published online 9 January 2008. doi:10.1038/mi.2007.19 116 VOLUME 1 NUMBER 2 | MARCH 2008 | www.nature.com/mi REVIEW heparin sulfate glycosaminoglycans8 and following binding most prevalent worldwide are serovars E, F, D, and Ia. 26 – 32 to a number of proposed ligands on Chlamydia (reviewed Serovar E is the predominant serovar in cervical isolates 33 in ref. 9). Once inside, the epithelial cell-surface antigens and urine samples34 but was found in only 6% of rectal of the EB appear to prevent fusion of the endosome with isolates. 33 lysosomes,10 allowing the EB to subsequently reorganize Individual serovars have been reported to differ among into the larger, replicative form of the RB. RBs successfully different groups of women 35 by geographic region 32 a n d a l s o divide by binary fission, filling the endosome that has now by specific racial groups. 36 A s y m p t o m a t i c C. trachomatis infec- become a chlamydial cytoplasmic inclusion. Multiplication tions are highly prevalent in young women, with genotyping then ceases after 48 – 72 h and nucleoid condensation occurs, results showing that serovars E, I, and D (in decreasing order) enabling the RBs to transform into infectious EBs. The EBs are were frequent in women aged less than 30 years, whereas sero- released from the cell and target new host cells for progression vars F, E, and G (in decreasing order) were found in a group of infection.11 of randomly selected patients (aged 17 – 68 years) attending an In females, Chlamydia targets the apical surface of polarized inner-city outpatient gynecological clinic.35 Significant dif- superficial columnar epithelial cells that are found lining the ferences in serotype distribution by geographic region in the endocervix and upper reproductive tract, an attachment that has United States were reported, with the rare serotypes Ba and G previously been shown to be enhanced in estrogen-dominant significantly overrepresented in San Francisco. 32 A more recent endometrial epithelial cells.12 study reported that blacks were less often infected with serovars Chlamydiae have the ability to cause prolonged and often sub- E (30 vs. 41% ) and J (9 vs. 24 % ) but more often infected with clinical infection. In vitro , it can be demonstrated that Chlamydia serovar Ia (17 vs. 0 % ) when compared with individuals of other can enter a latent state under stressful conditions such as expo- racial groups. 37 sure to interferon (IFN)- (which depletes available tryptophan), The association between serovars and infectious load was also exposure to penicillins, 13 growth in non-permissive cells,14 o r recently investigated. Similar infectious loads were reported for iron depletion. 15 This third or “ persistent form ” has been defined high-(E, F, and G) and low-(Ia, H, J, and Ja) prevalence serovars, as a viable but non-cultivable growth stage, resulting in a long- suggesting a similar ability for in vivo replication despite their term relationship with the infected host.16 Persistence allows differing ecological successes. 38 Men had a significantly lower C. trachomatis to remain dormant in the host cell, but after the load than women when the genotype was F, and the probability removal of stressful conditions, C. trachomatis can subsequently of being infected with serovar J was 7.7-fold higher in patients be recovered from culture. There is also accumulating evidence with prior chlamydial infections. 38 to support chlamydial persistence in vivo . 17 – 21 However, direct detection of Chlamydiae for the diagnosis of persistent latent Current antimicrobial therapy infection is somewhat questionable, and thus chlamydial per- Current recommendations of Centers for Disease Control sistence is not accepted by all researchers in the field, as many (CDC) for the treatment of C. trachomatis urethritis and believe that to demonstrate that chlamydial persistence occurs cervicitis are comprehensively covered in a recent review. 39 in vivo , both nucleic acid detection and viability of the organ- Compliance with an effective antibiotic regimen has neverthe- ism need to be proved. It is known that serological diagnosis of less reportedly been associated with an increased frequency of chronic persistent, latent infection can be somewhat imprecise recurrent infection, 20,40 tubal infertility, 17 and persistent infec- because of low detectable levels of specific antibodies, although tion characterized by a non-culturable but viable state in which recently it was reported that even very low levels of specific anti- RBs do not mature into EBs. 29,41 A n in vitro study of latent geni- bodies may be directly associated with a persistent infection.22 tal chlamydial infections using polarized human endometrial How often persistence occurs in vivo is unknown, but it may be epithelial cells reported that a persistent form of C. trachomatis that this persistence acts as an adaptive survival mechanism for did not have the same susceptibility to antibiotics as compared the organism. A review on chlamydial persistence has recently with actively growing Chlamydiae, with persistent Chlamydiae been published.23 phenotypically resistant to azithromycin.42 It has recently been hypothesized that women with high chlamydial loads may be Serovar distribution, clinical manifestations, and infectious at increased risk of antibiotic treatment failure,43 as it is known load that at high multiplicities of infection (load), in vitro resistance The major outer membrane protein (MOMP) and its gene can often be demonstrated to antimicrobials and genital load is ompA o f C.