Insight into Infection by Chlamydia trachomatis

Introduction

Chlamydia is the leading sexually transmitted infection (STI) among young men and women (WHO, 2018). There are approximately 127 million new infections of chlamydia each year; these infections are one of the major causes of pelvic inflammatory disease (PID) and infertility in women. The STI is typically just called Chlamydia, however, the infection in humans is specifically caused by the gram-negative bacterium Chlamydia trachomatis (Ct). The bacteria was discovered in 1907 by Halberstaedter and von Prowazek who observed it in an experimentally infected orangutan (Halberstaedter & von Prowazek, 1907). Infection by C. trachomatis presents as mostly asymptomatic, however, colorless mucoid vaginal discharge, hypertrophic cervix, and postcoital bleeding are symptoms sometimes seen in patients (Bebear & de Barbeyrac, 2009). Because patients with C. trachomatis urogenital infections don’t typically show symptoms, these infections often go undiagnosed and untreated. This can lead to more severe complications such as infertility, miscarriage, or ectopic pregnancy, a potentially life-threatening condition (Baud et al., 2011; Karaer et al., 2013; Kavanagh et al., 2013). Chlamydia is typically diagnosed via nucleic acid amplification tests using an endocervical or urine sample (Schachter, 2008). Though men do get infected with C. trachomati, it is more prevalent, and often times has more severe implications, in sexually active young woman in their late teens into their twenties, making women of this age group the most at-risk population.

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The reason I chose to write on this topic is because I truly believe in the value of sex education in schools. Coming to college you meet a lot of different people from a lot of different places who had completely different experiences, both educationally and personally. Though we all had common ground on a lot of our school curriculum, one area where there is a lot of variability is in sex education. Students such as my roommate had amazing access to sex education through their schools and were fully equipped for the world. Others, such as a couple of my peers whom I’ve recently discussed the matter with, were deprived of a comprehensive, in-depth sex education and were thrown into the world to learn on their own. The problem of sexually transmitted infections is very real for me and my peers, and there is a need for students like us to become more educated about these issues. As the leading STI in the world, I believed that Chlamydia was an appropriate topic to write about in the spirit of education on this matter.

Mechanisms of Infection and Immune Response

Ct exists in two forms: the infectious elementary body (EB) and the intracellular reticulate body (RB). Infection begins when elementary bodies attach to the epithelium of the urogenital tract. The EBs are taken up into the cell and in a few hours, change into RBs, which rapidly grow and divide. After this stage, RBs become EBs once again. After 2-3 days of infection, the host cell bursts, subsequently releasing the EBs which are able to attach to cells further in the urogenital tract and begin the process over again (Hafner et al., 2008; Zdrodowska-Stefanow, 2003). This cycle is demonstrated in the Figure 1 below.

        Figure 1. The life cycle of Chlamydia trachomatis (Zdrodowska-Stefanow, 2003).

Although there is no lymphoid tissue associated with the female reproductive tract, it does, however, have dendritic cells, macrophages and some resident lymphocytes which are throughout the fallopian tubes, uterus, cervix, and vagina (Givan et al., 1997). A typical Chlamydia trachomatis infection will typically appear in the lower genital tract. The innate immune system is the first line of defense against the infection. Pathogen recognition receptors (PRRs) and toll-like receptors (TLRs) on the host cells recognize the pathogen and pathogen associated molecular patterns (PAMPs) on the pathogen, triggering an immune response. The immune cells previously mentioned are recruited to the area of infection and infiltrate the epithelium of the affected tissue. This causes the epithelium to produce pro-inflammatory cytokines such as interleukin-1(IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα). These cytokines cause vasodilation, increased endothelial permeability, and recruitment and activation of neutrophils, monocytes, macrophages and dendritic cells (Zdrodowska-Stefanow, 2003).

 All of these cells are phagocytic cells which are responsible for phagocytizing the EBs that are released by decaying epithelial cells. This helps prevent the spread of the infection.

Macrophages and dendritic cells in particular play key roles in the control of the infection through release of cytokines IFN-γ and IL-12. These cytokines activate natural killer (NK) cells and induce the maturation of T cells. Cytotoxic CD8+ T cells play a role through induction of apoptosis of infected cells, though the greater role is in CD4+ T cells (Zdrodowska-Stefanow, 2003). CD4+ T cells either become T-helper 1 (Th1) or T-helper 2 (Th2) cells. In the infected area, there is a strong inflammatory reaction mediated mainly by Th1 cells to clear the infection (Loomis & Starnbach, 2002). These cells, in addition to the natural killer cells, produce interferon-γ (IFN-γ).  This leads to inhibition of chlamydial reproduction (Perry et al., 1997). IFN-γ is able to kill and inhibit the growth of Chlamydia through several mechanisms. For one, IFN-γ has been shown to enhance the phagocytic capabilities of macrophages (Fernandez-Boyanapalli et al., 2010) and promote the engulfment and elimination of Ct (Zhong & de la Maza, 1988). It has also been shown to downregulate the transferrin receptor (Ryu et al., 2000), which is needed for the import of iron into the cell. Iron is one of the key nutrients needed by many bacteria, and unsurprisingly, has been shown to be key to the survival of Chlamydia trachomatis (Al-Younes et al., 2001). By limiting the availability of iron, IFN-γ is able to inhibit Chlamydia growth. Another mechanism of action for IFN-γ is through degradation of tryptophan, which most Chlamydia species require for survival (Akers & Tan, 2006). IFN-γ induces the expression of the enzyme indole 2,3-dideoxygenase (IDO), which degrades tryptophan, leading to death through tryptophan starvation (Beatty et al., 1994).

 Though the Th1 CD4+ cells are of greatest importance to clearance of Chlamydia trachomatis infection, B cells also play an important role in modulating immunity via several mechanisms. The first is through antibody-mediated neutralization. In this mechanism, B cells produce specific antibodies against chlamydial peptides (Bartolini et al., 2014). Secondly, cells with attached antibodies are targeted for lysis through antibody-dependent cellular cytotoxicity (Moore et al., 2002). Lastly, B cells help form antibody–antigen complexes that bind to receptors on antigen-presenting cells, enhancing phagocytosis and antigen presentation to T Cells, most specifically Th1 cells, leading to the response previously mentioned above (Igietseme et al., 2004).

To note, the most commonly used animal to research Chlamydia, and the model used in most of the research cited in this paper, is the mouse. In addition to mice, pigs, pig-tailed macaques, and guinea pigs are also commonly used, but not nearly to the extent of the mouse model. For studies in mice, C. muridarum is utilized because C. muridarum intravaginal infection produces very similar results to that of acute C. trachomatis infection in women. The C. trachomatis strain is also used in mice; however, the infection is less severe and is typically easier to treat than a C. muridarum infection. Therefore, most of these studies used mice infected with C. muridarum (De Clercq et al., 2013). This information is here to provide some context and address some possible shortcomings on the findings of these papers. In the future, use of humanized transgenic mice infected with C. trachomatis may prove to be the most effective model.

Management of the Infection

Persistence of and reinfection by Chlamydia trachomatis is common. Reinfection will typically induce a strong secondary immune response which leads to increased inflammation. This may potentially lead to further damage to the reproductive tract, as is the case with chronic pelvic inflammatory disease. Further spread of the infection into uterus and Fallopian tubes raises the risk of ectopic pregnancy and infertility (Hillis et al., 1997). In order to treat and prevent the further spread of the infection, detection and treatment must happen as early as possible.

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Suggested treatment for uncomplicated urogenital chlamydial infection in adults is the antibiotics azithromycin and doxycycline. In pregnant women, the suggested treatment is the antibiotic amoxicillin (Miller, 2008). Azithromycin and doxycycline both inhibit bacterial protein synthesis by binding to and interfering with the assembly of the 50S and 30S ribosomal subunits respectively (Parnham et al., 2014; Chopra & Roberts, 2001). Amoxicillin works against Ct. by inhibiting cell wall synthesis, leading to cell lysis (Bush & Bradford, 2016). Though treatment with antibiotics appears to be effective, unfortunately, a quarter of affected individuals are reinfected within a year after treatment (Vasilevsky, 2014).

In terms of other forms of treatment and prevention, vaccines have been looked at with hope, though neither a fully nor partially protective vaccine has been developed ((Vasilevsky, 2014). Attempts at developing a vaccine to Ct. began with whole organism vaccines, though these studies have demonstrated poor results (Grayston et al., 1963; Sowa et al., 1969). The most promising live vaccine comes from a study in which mice were vaccinated intravaginally with an attenuated strain of C. trachomatis (Olivares-Zavaleta, 2010). However, its effectiveness was proven to be limited to a short time period after infection. And in general, live vaccines pose a risk to the recipient, as there is always the potential for the bacteria to revert to its virulent form, and as such, other forms of vaccines are more likely to be utilized. In terms of killed or inactivated organisms for vaccines, not many studies have been done. This is due to the need for a strong immune response, something an inactive organism is typically unable to elicit.

Following the use of whole-organism vaccines came the use of subunit vaccines. In 2000, researchers were able to develop a relatively successful vaccine using major outer membrane protein from Ct. to elicit a Th1 antigen-specific immune response that lead to clearance of infection by immunized mice (Igietseme & Murdin, 2000). Although the desired response was achieved, this can only be termed “relatively successful” considering that it would be very expensive and unfeasible to make these vaccines commercially available, rendering them mostly useless for the purposes of solving a public health issue such as this (Schautteet et al., 2011).

Another potential vaccine candidate could be a DNA vaccine. The idea is that plasmid DNA encoding a foreign gene of interest be injected inside the host, resulting in expression of the foreign gene product. This foreign gene product would subsequently lead to an immune response from the host (Schautteet et al., 2011). This kind of vaccine would provide the benefit of an attenuated vaccine by providing multiple immunogenic epitopes that trigger both humoral and cell-mediated immunity without the risk of reversion to a virulent strain. Though some attempts at such a vaccine have seen failure (Pal et al., 1999), others have proven to have potential (Ifere et al., 2007).

Summary/Conclusions

As discussed above, Chlamydia trachomatis is among the most prevalent of the sexually transmitted infections, affecting over 100 million people each year. Infection by Ct. is very much a danger and a threat to public health, as it often goes unnoticed by the infected, giving it the opportunity to spread within and amongst individuals. Though treatment is possible through antibiotics, the rate of reinfection is alarmingly high. Despite the large and prevalent impact made by Chlamydia trachomatis, there is still yet to be a viable vaccine. Though great strides have been made in developing a vaccine, there is a far way to go before there is a candidate vaccine that has true potential to combat this public health issue. A mathematical model developed in 2009 demonstrated that theoretically, if an entirely effective vaccine were to be administered to 100% of male and female adolescents before they were sexually active, Chlamydia trachomatis infections would be gone in less than 20 years (see Figure 2). Even with only 50% of males and females being vaccinated, the prevalence of Chlamydia trachomatis would be at approximately 0.5% after 20 years (Gray et al., 2009).

Figure 2. Effects of coverage rates before sexual debut on the prevalence of chlamydia infection (Gray et al., 2009).

This clearly shows the power of and need for development of a vaccine against Chlamydia trachomatis. In the meantime, what needs to happen to help control the spread of Ct. and to help people catch the infection before it leads to something more severe is to make screening a more regular activity that we partake in. Many people, and most often young people, believe that they are untouchable and that an issue like this doesn’t apply to them. However, there is no guarantee that someone’s sexual partners are STI/STD free, and if there is even the tiniest amount of doubt in someone’s mind about the safety of their sexual encounter, they should go in to be tested for the sake of their own safety and the safety of others.

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