Chlamydia: The Secret Enemy from the Past to Present, and Future

Abstract

Chlamydia was discovered in 1907 by Halberstaedter and Von Prowazek in conjunctival scrapings from an experimentally infected orangutan. Once being thought of as symbiont in plant like unicellular amoebae to intracellular parasites of vertebrates to viruses to currently as obligate intracellular bacteriae. Chlamydia is able to survive indefinitely as viable but non cultivable altered forms being a bacteria. It’s a supremely adaptable microorganism as seen with the emergence of it’s Swedish New variant (nvCT) in 2006, which was not a product of mutation or recombination but due to losing a short segment of DNA from it’s plasmid. The disease expression of Chlamydia is due to the interplay between the differences in the plasticity zone of it’s genome and the host factors. Despite the recombination of genes and emergence of new variants there is no evidence of circulating genomic resistance in Chlamydia trachomatis. The ‘seek and treat’ Chlamydia control strategy shortens the genital infection yet it’s rising sequelae of tubal infertility, the evidence of neoplastic change in cervix via modulation of caveolin-1 and c-myc RNA expression and it’s under investigated role in pathogenesis of atherosclerosis and ischemic heart disease is a sign of how exponentially this organism is evolving.

1. Introduction

Humans have bravely faced this magically cloaked organism since the past till present; and their efforts to deal with it in the future are still going on strong. They are dwelling worldwide among livestock, humans and free-living animals. The true color of Chlamydia will be discussed as how secretively it has spread its roots among humans playing constant hide and seek with us without our suspicion. One chapter is never enough to talk about Chlamydia and how it might soon get the status of being omnipresent. Our hope is not only to touch upon its journey from past to present as concisely as possible, but also to express our views about conjoined future with us. Before talking about the present scenarios, we need to understand about the organism first.

2. Chlamydia: the organism

The phylum of Chlamydiae has obligate intracellular, Gram-negative bacteria. They consist of the following four groups (Simkania, Waddila, Chlamydiaceae and Parachlamydia family) with five added Candidatus families (Parilichlamydiaceae, Clavichlamydiaceae, Rhabdochlamydiaceae, Criblamydiaceae, and Piscichlamydiaceae) [1]. Literature search tells us that chlamydia like caused diseases in the eye have occurred in ancient Egyptian papyri (1555–1553 BC) and Chinese writings (2700 BC). The associates of Albert Neisser, von Prowazek and Halberstaedter, noticed inclusions within the cytoplasm of cells in the scrapings of conjunctiva, from patients with trachoma in 1907. Chlamydiae was isolated by Levinthal, Cole and Lillie between 1929 and 1930 while they were studying psittacosis. It was described as a virus by Bedson an Bland in 1932 [2]. Earlier chlamydiae were considered to be protozoa in 1997 as chlamydia-like microorganisms were first found in single-celled, free-living environmental acanthamoebae [3]. Then as they passed through filters of 0.45 μm diameter and had a biphasic intracellular development cycle, they were thought of as viruses. However, as it had- both RNA and DNA, the ability to synthesize nucleic acids, proteins and lipids, the susceptibility to antibiotics; hence they were concluded as bacteria. However, as they are obligate intracellular pathogens, they are cultivated only within living cells, unlike free living bacteria [2].

At present there are 16 species put forward in the Chlamydiaceae family, which infect a broad range of hosts and different anatomical sites. Out of which humans are primarily infected by C. trachomatis and C. pneumoniae, with C. psittaci having proven zoonotic potential in humans [4].

C. trachomatis remains an elusive human infecting species constantly under focus. It consists of four ocular serovars A, B, Ba, and C that cause endemic trachoma, with at least eight serovars, D to K, that cause infections of the genital tract. In addition three L serovars are also included that cause lymphogranuloma venerum. Genome sequencing helped in knowing this enigmatic organism more. An early study on genomic phylogeny described the “trachoma clade” in which C. trachomatis is divided into two distinct clades of LGV and the ocular and genital tract isolates [5]. This clade has two lineages (T1 and T2). Clade T1 includes more common urogenital isolates, whereas T2 contains rarer urogenital isolates and ocular strains, that makes this cluster, making one suspect that these ocular isolates could have emerged from a urogenital ancestor. It is suspected that chlamydiae spread further from a urogenital niche to infect the eye, resulting in trachoma [6]. This notion evolves from the ability of urogenital isolates to utilize indole and synthesize tryptophan that is abundant in the vagina due to it’s microbiome, but ocular strains lack this ability. Hence, urogenital strains can flourish both in the eye and genital tract, whereas ocular strains fail to thrive in the genital tract [7]. Myths like, C. trachomatis is a parasite as it derives energy from the eukaryotic host cell have been quashed with the help of genome sequencing with the discovery of all the required genes for the biosynthesis of ATP [8].

Over the years Chlamydiacae family evolved to give rise to new variants, serovars and species and humans have discovered new species as well while studying this organism over the years. The process of Lateral gene transfer (LGT) influences bacterial ecology and pathogenesis of diseases, evolution of Chlamydia and the propagation of antibiotic resistance across different species. Also known as Horizontal gene transfer, it involves genetic material (DNA) transfer between the cells followed by it’s integration into the recipient cell’s genome. Mutation is not the only adaptive strategy of C. trachomatis to evolve. High recombination rates among the strains seen using phylogenetic analysis of genomes, tell us otherwise. The overall average recombination rate seen has been around 26% (5–32%) [9]. The phenomenon of intrastrain recombination among C. trachomatis was first reported in literature, in the 1990s. It was based on gene-specific sequence analysis of gene ompA, that is responsible for synthesis of major outer membrane protein (MOMP). A wide range of such regions with high recombination rates are present in C. trachomatis and C. pneumonia like ompA, tarp (the translocated actin-recruiting phosphoprotein encoding gene), the polymorphic membrane protein-encoding genes (pmps), and incA, as well as the plasticity zone (PZ). Studies show that recombination events keep occurring across the complete genome leading to evolution of C. trachomatis as well as other chlamydial species such as C. pneumoniae, C. suis and C. psittaci. Cross-species and intraspecies genetic transfer vary. Intraspecies LGT maintains wild-type genomes within the cell, that otherwise might be considered stressful and mutagenic [10]. Whereas interspecies recombination leads to replication termination. It is now possible to genetically modify the organism, as evident in knockout mutants where the genes that are involved in LGT are inactivated [11].

The more we write about it and understand this organism, more is the number of doors we see that take us forward to amazement.

3. Chlamydia and it’s rainbow spectrum of diseases

Chlamydia was recognized as STI in the 1970s, became notifiable in the year 1988. New cases were reported routinely in the STI statistics 1990 onwards. After 1995 the noted cases then began to rise steeply [12]. More number of couples started seeking infertility treatment. It became a disease which was turning into a direct threat for the propagation of life on earth. How could the human attention not go towards this gram-negative bacterium then, that has made humans err a lot in its identification as a bacteria. Gradually, more research has unveiled a lot of diseases where intensity of the role of chlamydia is still under constant scrutiny.

Table 1 is known hosts and their corresponding infective species of the Chlamydiaceae family.

Primary host	Species	Disease site
Human	C. trachomatis	Urogenital, ocular
Bird	C. psittaci	Respiratory and placenta
Human	C. pneumonia	Respiratory
Pig	C. suis	Urogenital, ocular
Cat	C. felis	Urogenital, ocular and respiratory
Livestock	C. abortus	Placenta
Mice	C. muridarum	Urogenital
Guinea pig	C. caviae	Urogenital, ocular and respiratory
Bird (pigeon)	C. avium	Respiratory
Marsupials, livestock	C. pecorum	Urogenital and conjunctiva
	C. ibidis
	C. gallinacean
Snake	C. serpentis	Cloacal, choanal
	C. poikilothermis
	C. corallus

Table 1.

Host, Chlamydia infective species & their disease sites.

The information in Table 1 is an established limited knowledge. Multiple reports and research are continuing to highlight the involvement of Chlamydia.

Chlamydia has not spared the newborns. Many infants infected with C. trachomatis at birth have remained so for long period of time without appropriate antimicrobial therapy. This may misdirect us to sexual abuse. The cumulative infected proportion of infants at 1 year of age has been noted to be 35% [13]. The account of longest persistence of infection in one child, in the conjunctiva, nasopharynx, and oropharynx, has been around 866 days (28.5 months), until treatment cured it. Same serovars of C. trachomatis were reported in specimens from infants and their respective mothers and the serological tests in all infants pointed to the acquisition of infection during birth only [13].

Genital Chlamydia infection: In women it encompasses mucopurulent cervicitis, urethritis, and endometritis. Mucopurulent cervicitis can complicate into—salpingitis, pelvic inflammatory disease (PID), tubal pregnancy, chronic pelvic pain, Fitz Hugh Curtis Syndrome; premature rupture of membrane during pregnancy, chorioamnionitis, premature delivery, puerperal and neonatal infections (like conjunctivitis and interstitial pneumonia) and recurrent spontaneous abortions due to its immune reactions in human body. It’s considered to be the leading cause of infertility. Around 20–30% of PID cases have been accredited to C. trachomatis in USA [14]. A study from India reported the prevalence of C. trachomatis infection around 23% in gynecology OPD (outpatient department) [15] and around 19.9% of total STD patients [16]. In a systematic literature review from India, the rate of prevalence among infertile women was reported as 9–68% based on PCR results which took into account mostly the urban metro cities with only two studies from rural settings [17]. The reason that Chlamydia is an intense threat because, a large reservoir of unknown infected transmitting sources exist while leaving everlasting sequelae. Around 70–80% of females and up to 50% males carry asymptomatic infection [18]. Urethritis and epididymitis is on the male spectrum of genital chlamydia. An uncommon complication of untreated chlamydial infection is Reiter’s syndrome, that is more common in females. Intra-articular C. trachomatis infection has been found in seronegative spondyloarthropathies using PCR [19].

In the past there has been a huge buzz around female infertility caused due to it, continuing till present. What about male infertility? C. trachomatis can lead to male infertility because it causes epididymitis and, consequently prostatitis and orchitis in them. According to Sonnenberg et al., Chlamydia infection can directly damage the sperms as well [20]. It can also cause testicular atrophy and obstructive azoospermia.

STIs are generally known to have good camaraderie with each other. Chlamydia is no exception here to our dismay. C. trachomatis infection increases risk of acquiring Human Immunodeficiency Virus infection, it’s transmission by 3 to 4 fold and flourishes as co-infection with human papillomavirus (HPV) as well [21, 22]. But this is not a synergistic association. In study done by Martinelli et al., no association was observed between presence of C. trachomatis and abnormal Pap smear. In the study, C. trachomatis and HPV co-infections were seen in 4.9% and 9.3% of patients with and without cervical cytology abnormalities respectively [23]. This prevalence figure is in line with the rates previously reported in the literature. The prevalence of chlamydia was more in the normal cytology ones. But one cannot deny that, the co-existence of the C. trachomatis and HPV 16 might increase the risk of cervical carcinoma [24]. The carcinomatous changes are more profound with co-infection as compared to mono-infection in various studies. It’s intriguing that, the load of C. trachomatis DNA has been found to be significabtly higher in cases of co infection as compared to mono infection. This points out to how the relationship between Chlamydia infection and the host immune response makes the foundation to understanding the disease process.

Chlamydia has been implicated in the causation of diseases where its role is still under question and research. Extragenital manifestations of chlamydia have come up with changing societal behavior and acceptance, as compared to the limited data and prevalence in the past. Most extragenital infections in women remain asymptomatic, estimated at—100% of pharyngeal chlamydia, 36–100% of rectal chlamydia, 93% of pharyngeal gonorrhea and 53–100% of rectal gonorrhea [25]. Rectal gonorrhea or chlamydia without history of anal sex has been reported in a significant number of women. Extragenital infections are higher among MSM. The prevalence in MSM (Men who have Sex with Men) ranged from 2.1 to 23% for rectal chlamydia (median 8.9%), 0.2 to 24% for rectal gonorrhea (median 5.9%), 0 to 3.6% for pharyngeal chlamydia (median 1.7%) and 0.5 to 16.5% for pharyngeal gonorrhea (median 4.6%) [26]. The prevalence of extragenital infections among MSW (HIV positive Heterosexual Men) in the studies reviewed ranged from 0 to 11.8% for rectal chlamydia (median 7.7%), 0 to 5.7% for rectal gonorrhea (median 3.4%), 0 to 22.0% for pharyngeal chlamydia (median 1.6%) and 0.4 to 15.5% for pharyngeal gonorrhea (median 2.2%) [26]. C. pneumoniae has been shown to have synergistic association with development of Coronary Artery Disease, with higher rate of positivity for C. pneumoniae IgA than IgG in positive PCR of CAD patients [27]. C. pneumoniae antibody positivity has been found to be independently associated with ischemic stroke in elderly patients without altering stroke outcome [28]. Chlamydia pneumoniae also has role in childhood asthma. In a study, anti-C. pneumoniae IgM was positive in 25% of patients with uncontrolled and partly controlled bronchial asthma [29]. Also duration of hospital stay was found to be longer in patients of uncontrolled asthma who had anti-Cp IgM positive [29]. C. pneumoniae IgG antibody has been found to be independently associated with migraine in Indian patients [30]. C. trachomatis has been proposed to play a role in photosensitive dermatoses and melasma, with variable positivity for IgA, IgM and IgG antibodies to C. trachomatis [31, 32].

Chlamydia has risen like a huge eagle from past to the present and humans are yet counting the feathers. Mankind does not know the extent but indeed it will be and it has to gear up to face chlamydia.

4. The journey of diagnostics for chlamydia

The diagnostic methodology of chlamydia has undergone a transformative change over the last two decades spanning from the traditional culture to high throughput NAAT (nucleic acid amplification test)/NGS (next generation gene sequencing). Testing for chlamydia infection is indicated for patients having ocular, urogenital and anorectal symptoms. Close contacts of such patients should also be tested for chlamydia and other sexually transmitted infections along with medico legal cases destined for such testing.

Laboratory investigations include both direct and indirect methods. Direct methods depend on detection of the antigen or nucleic acid. It includes culture, antigen tests (Enzyme Immune Assay, direct fluorescent antibody (DFA), and immune chromatographic RDTs), nucleic acid hybridization and amplification tests. Indirect methods detect antibodies against CT and have a role in diagnosing chronic and invasive infection like pelvic inflammatory disease (PID), lymphogranuloma venerum (LGV) and post infectious complications, like sexually acquired reactive arthritis (SARA) [33]. As C. trachomatis crosses the epithelial barrier and may no longer be detectable in swabs in these chronic/invasive infections. However, serology is not recommended for diagnosis of acute genitourinary infections, as the antibody response comes into play only after weeks to months of infection and the titers are usually insignificant.

4.1 Individual methods

4.1.1 Cell culture

“Cell lines for isolation of C. trachomatis include Mc Coy, HeLa 229 or Buffalo Green Monkey Kidney cells” [33]. Swabs are taken from different anatomical sites (endocervix, urethra, anal canal, conjunctivae) and inoculated. However, swab collection requires special collection device and transport media as culture can detect only viable organisms. “The detection rate is around 60–80%, in reference laboratories with experienced technicians” [33]. Limiting factors for culture include extended turn-around time, intensive labor requirement and difficulties in standardization. Hence cell culture is remotely used nowadays, however it has an important niche in reference laboratories and in few conditions like to monitor antibiotic susceptibility and change in virulence.

4.1.2 Nucleic acids amplification tests (NAATs)

NAATs have replaced culture as the diagnostic gold standard as they have high sensitivity and specificity and are currently the standard of care in diagnosing CT infections. With introduction of dual-target assays which incorporates a 2nd target region in NAATs the detection of new variants with deletions or recombination in one of the target regions is possible. Use of coated magnetic beads for nucleic acids isolation in the pre analytical steps also enhances the diagnostic sensitivity [34]. “These bead-based extractions systems allow simultaneous testing of chlamydia and gonococci with high sensitivity and specificity, can be automated and are used in several high-output systems” [33].

4.1.3 Clinical specimens required for CT testing

NAAT can analyze any clinical material like vulvo-vaginal, anorectal, urethral, cervical, ocular swabs, first void urine (FVU), sperms or living tissues. FDA approved NAAT’s are available for first void urine, urethral, vaginal and cervical swabs. For screening asymptomatic individual’s noninvasive specimen like first void urine is preferred. In contrast to collection of urine for routine culture sensitivity for other organisms where mid-stream sample is preferred, for chlamydia detection first void urine is recommended as the concentration of chlamydia sharply decreases during urination. Genital swabs are preferred in women as the CT concentration is comparatively higher when compared to urine. “A study analyzing urine, vaginal and cervical swabs taken simultaneously from asymptomatic women showed that the NAAT detection rate was highest in self-collected vaginal swabs. Hence, vaginal swabs (self-collected or clinician-collected) are the recommended sample type for women. Endocervical swabs may also be used, especially when a pelvic examination is indicated” [33].

For detection of extra genital infection like conjunctivitis, pharyngeal or anorectal infections, testing of corresponding swabs or tissue samples is recommended.

4.1.4 Recent developments

Proteomics are also being deployed in CT detection with encouraging results. These results might be used to characterize antibodies specific to detect different stages of infection.

“The Management of Chlamydia Cases in Australia (MoCCA) study is a new initiative to address gaps in chlamydia management in Australian general practice through implementing interventions shown to improve chlamydia management in specialist services. MoCCA will focus on improving retesting, partner management including patient-delivered partner therapy) and PID diagnosis” [35].

“Accelerated partner therapy contact tracing for people with chlamydia (LUSTRUM): a crossover cluster-randomised controlled trial results suggest that accelerated partner therapy can be safely offered as a contact tracing option and is also likely to be cost saving” [36].

5. Treatment and control: how far have we come?

Well we have come far in understanding Chlamydia. Once surprised humans by its lack of peptidoglycan in its structure yet being sensitive to penicillin [37]. Years later research revealed that unlike other bacterial species, members of the Chlamydiacae do not synthesize Peptidoglycan (PG) in their cell wall or “sacculus” but their PG is maintained in a narrow band that corresponds to the plane of septal division [38]. This PG “ring” has an active role in cell division of Chlamydia [39]. It is therefore included in the group of ‘peptidoglycan-intermediate’ organisms. Other such organisms are the Wolbachia, Orientia tsutsugamushi and Anaplasma marginale [40]. Peptidoglycan is a potent stimulator of the immune system and Chlamydia has perfectly cloaked it once to be a mystery for quite some time.

Treatment was targeted using the initial available antibiotics such as penicillin, amoxicillin in 1970s. Penicillin did not eradicate C. trachomatis but did inhibt its inclusion formation in in vitro studies when added within 1 h [41]. Amoxicillin 10 day course did eradicate it (unpublished observations of W. R. Bowie, E. R. Alexander, and K. K. Holmes). Gentamicin, Streptomycin, metronidazole and nalidixic acid were inactive against C. trachomatis. Tetracycline and erythromycin exhibited poor effects clinically, with good in vitro activity. In vitro under all tested conditions, doxycycline, minocycline and rifampin were more efficacious than tetracycline. The emerging most effective antimicrobial agent was turning out to be doxycycline [42].

In 1990s a new azalide antibiotic azithromycin was found effective both in vitro and in vivo; with ability to block formation of elementary bodies [43]. Azithromycin and doxycycline were then extensively investigated various studies and experiments. Studies reported Single dose azithromycin superior to 3 days course of doxycycline for various species of chlamydia [44]. Mass drug administration (MDA) of single dose of Azithromycin began to be employed widely for trachoma as part of its elimination strategy. Later studies emerged which reported that single round of MDA brought down the overall active trachoma prevalence but had no influence on ocular C. trachomatis infection [45]. MDA of azithromycin has shown to be inadequate when encountered with heavy infection load, and this leads to persistence of infection post MDA. There is concern that MDA can lead to development of resistance in other organisms, notably Streptococcus pneumoniae. This is not after single round of MDA, but multiple rounds [46]. The first report of persistent or relapsing infection due to multidrug-resistant C. trachomatis came forward in year 2000. All 3 isolates in the report demonstrated resistance to azithromycin, ofloxacin and doxycycline at concentrations >4.0 μg/mL [47].

Azithromycin rapidly rose as the choice of treatment because of its less frequent dosing and high efficacy, was incorporated in trachoma elimination strategy. In 1998 Centers for Disease Control recommended Azithromycin as the first-line therapeutic regimen to treat genital infections in women and men. But then came growing emergence of resistance to it in urogenital and rectal isolates. Its detailed pharmacokinetics study unearthed the reasons for its new challenges. The action of azithromycin being pH dependant, unionized at high pH and only unionized form can go intracellular. It needs polymorphonuclear cells to be transported to the site of inflammation. More bacterial load is reported in rectoanal samples than endocervical. Higher MIC values have been found for Azithromycin in these samples, almost 2 fold higher.

A double blind RCT (2021) in 177 participants reported a “1-week course of doxycycline was significantly more effective than a single dose of azithromycin for the treatment of rectal CT in MSM” [48]. It is a conundrum that a significant proportion of women, with no history of anal intercourse, have asymptomatic rectal chlamydia infection. In what way this will influence the treatment in women is still unfolding. There is a theory that this rectal infection might be a “reservoir for reinfection of the vagina and sexual transmission” [49]. Hence antibiotic that tackles the rectal Chlamydia trachomatis is the need of the hour [50]. For the same STI, same antimicrobial or same regimen of dosing might not be the answer for different sites of infection in the body.

More research and trials, and the limitations with azithromycin are taking us back to Doxycycline when it comes to C. trachomatis. Doxycycline is promising even when used as a prophylaxis to prevent bacterial STIs as seen in short term RCTs and clinical studies, but robust evidence is still in need for this [51]. The target population for this need of prophylaxis is MSM, which would also help in less transmission of HIV by maintaining the mucosal integrity that gets broken which allows easy transmission of HIV and vice versa.

But the challenges are increasing each day when it comes to fight with CT. In a study from India that investigated isolates from females with recurrent chlamydial infection, decreased susceptibility to the present first line antibiotics (doxycycline and azithromycin) was noticed [52].

There is indeed a compelling need to research more about the antimicrobial resistance mechanism. There are two types of resistance that have been seen in Chlamydia species- homotypic and heterotypic. In homotypic resistance the organisms mostly survive above MIC (Minimal Inhibitory Concentration) of the antibiotic, whereas in heterotypic less than 1% of the organisms can survive above MIC [53]. “Azithromycin resistance of C. trachomatis is often a result of the mutations in the peptidyl transferase region of 23S rRNA genes, tetracycline resistance is usually linked to the presence of foreign genomic islands integrated in chlamydial chromosome, a predominant mechanism of fluoroquinolone resistance is a point mutation in the gyrA quinolone-resistance-determining region. A nucleotide substitution in rpoB gene is responsible for rifampin resistance” [54].

As we have no effective new antimicrobials for STI on the horizon, there is a dire need to optimize the use of available antibiotics with respect to their dose, regimen of dosing and their simultaneous use with other antibiotics.

Humans have been devising new control strategies continuously. SAFE has been able to decrease the load of trachoma very well. But when it comes to urogenital and rectal Chlamydia, the screening approaches have their pros and cons. It’s still a debate whether universal screening or targeted screening is the solution. Universal screening is indeed obviously more effective, but the question is- is it cost effective?

Who to screen and how is still being subjected to multiple studies and reviews in order to frame the best pronged guidelines. Among 18–31 years old women, Mehta et al. observed that a greater number of PID cases were prevented by screening (universal and selective) using Ligase Chain Reaction (LCR) in urine for chlamydia and gonorrhea as compared to the usual practice of treating only self-reported or symptomatic cases [55]. Combining both standard procedure and screening turned out to be more cost effective in women, as the sequelae affect them for their future lives. Whereas in men the standard method of treating detected cases was better with respect to the cost involved, when compared to enhanced screening [55].

Mass Drug Administration has proven quite useful in control of trachoma, but the frequency of it depends on the prevalence and transmission rates in the area targeted. In high prevalence areas with trachoma annual MDA is not enough, quarterly MDA has been thought as a better control strategy. When it comes to urogenital and rectal Chlamydia control, the acceptability of MDA is not established. Pre-exposure prophylaxis in population at risk e.g. MSM has reduced transmission in pilot studies [56]. Also the impending threat of antibiotic resistance always prevails.

While talking of control practices one thing that should never be missed is safe sexual practices and stress over sex education from early adolescent life can be the best cost effective strategy.

6. The future of chlamydia

The past had unfolded to become the present and the present will continue to unfold into the future. Hence looking at the evolution of different aspects related to chlamydia from past to present, let us see what we might see at the forefront in future.

With rapid discoveries of new chlamydial species, there is definitely increasing risk of zoonoses in humans. Chlamydia psittaci—the causative microorganism of ornithosis, is the most well-known zoonotic pathogen. Chlamydiae are quite prevalent microorganisms in the animal kingdom. Constant human exposure via research keeps us always on the verge of contracting zoonoses.

Despite more than 20 years of screening programme and chlamydia testing in many countries and regions, chlamydia control strategies still rely on assumptions rather than robust evidence. The trend is shifting from the approach of diagnose and treat to more focused management of patients and their partners [57]. The focus is on management of disease rather than management of infection. A wide array of approaches are being proposed and tested for chlamydia control.

On one hand there’s this notion developing regarding early antibiotic intervention programme and pre exposure prophylaxis in at risk population. A randomized study under “Ipergay trial” done in the MSM group used doxycycline prophylaxis that consisted of two doses of the drug administered after the sexual encounter within a period of 72 h. It reported that Doxycycline Post Exposure Prophylaxis decreases the incidence of a first symptomatic bacterial STI in at risk MSM [58]. Yet on other hand early antibiotic intervention strategy may have undesirable impact of reducing the herd immunity as it eliminates “bottlenecks to Chlamydia transmission” among humans [59].

Macrolides, quinolones and tetracyclines are the usual antimicrobials used to treat acute Chlamydial infections. However, Chlamydiae can develop “persistent forms (atypical reticular bodies)” that remain uninfluenced by usual available therapies [60]. This is not genetic resistance, but actually is phenotypic resistance. Persistent infections can turn to have clinically chronic courses.

So many questions and doubts revolve around antibiotics. One answer is leading us to the next new question. Hence there was a need to look at other options to battle with chlamydia. The focus is around a vaccine, alternative therapies for chlamydia and educating humans for being responsible for their sexual behavior. A vaccine for chlamydia carries the hope of an ideal protective strategy. Why is there an evolving urgent need of vaccine against chlamydial infection? An infection that has accessible antibiotic treatment but behaves exactly like its name—a cloaked organism. A magical cloak that allows it to spread rapidly, create new variants, have high rates of re-infection, be asymptomatic so often yet lead to drastic sequelae that has potential to change the nature’s human anatomy and physiology by rendering it infertile or play a probable role in carcinogenesis! Accessible treatment, screening programmes and awareness programmes leading with—“Chlamydia is not a flower” have not been enough! The quest for an effective vaccine has utilized multiple chlamydial species and their different antigens. The trajectory of different antigens has included whole cell and subunit vaccines—utilizing Major Outer Membrane Proteins, Polymorphic Membrane Proteins, Plasmid antigens etc. MOMP has shown promising results. The challenge in the vaccine development has been it’s mucosal protective immunity and robust immune response. After more than 70 years of several vaccine trials, first in human vaccine trial via both intramuscular and intranasal routes, has reported good immunogenicity with good tolerability. “Antigen CTH522 with either CAF01 liposomes or aluminium hydroxide (AH)” as adjuvants were studied, where liposomal adjuvant formulation had a better profile [61]. A variety of alternative therapies are also being utilized to derive whatever benefit they might provide. Non antibiotic approaches include synthetic drugs like “Broad-Spectrum Antiviral Compound ST-669”, a “small-molecule inhibitor of type III secretion INP0400”, “Lipopolysaccharide-Binding Alkylpolyamine DS-96”; polyphenols like “Baicalin, luteolin and catechins”. Peptides like “Transferrin”, “WLBU2 Peptide”, “Cecrotin peptides”, “Cathelicidin peptides”, “Spider venom peptides” etc. have also shown slow therapeutic effect. The hurdle with these alternative therapies is that they are needed in high concentrations where they have unpredictable efficacy [62]. Vitamin E supplementation has shown increased humoral response towards chlamydia [63]. Interferon and interferon inducers have shown reduced growth of chlamydiae in vitro, when subjected to it six or eighteen hours prior to infection, and when treated early (within four hours) after infection reduced yield was detected in the cell cultures [64].

Recently the interest has spiked in anti-infective drugs that disarm the organism and help the host immunity in clearing infection. This surpasses the hurdle of antimicrobial resistance. For example—small-molecule LpxC inhibitors blocks the synthesis of lipopolysaccharide in Chlamydia due to which it replicates within vacuoles intracellularly, but cannot transition into the invasive form—“the elementary body”. Yet there is time for further development of such drugs and whether they can be commercially viable therapeutics [59].

Single measures or a few combined measures are not what will help control Chlamydia. Impeccable efforts to develop a plan with designed steps, is the need for any major success. An “Integrated Care Model with Implementation Roadmap to Improve C. trachomatis Management and Control” has been developed in India [65]. It focuses on 4 key areas- Awareness, timely and effective management, aggressive follow up, and prevention. In developing countries the barriers to Chlamydia control narrow down to two main categories—Logistics & Resources and Culture & Education.

It is seen that younger age has higher association with C. trachomatis infection prevalence, due to more risky sexual behavior. Hence the role of timely sex education in pre-adolescence or adolescence with sufficient information about such STIs and the protection measures could lead to a more responsible and informed young adult population. This could culminate into a healthier thriving young population over the years [66].

7. Conclusions

Humans have come forward extensively from past to the future; when it comes to knowing the organism Chlamydia as discussed in the chapter, the range of diseases it causes, the development of diagnostic techniques we have to detect it and understand it further, the journey of finding the best treatment options to tackle it, the realization of the need of a preventive strategy before treatment strategy, the celebrated steps towards developing a vaccine, the development of comprehensive plans to instill an inclusive programme that aims to control the spread of chlamydia and hence to stop the further sequelae and it’s impact on human race with a little peek window into the expected future of chlamydia and humans.

Acknowledgments

I Dr. Saurabh Krishna Misra would like to express my special thanks to my wife Dr. Richa Dokania Pedodontist for her constant encouragement thought the journey and Dr. Ankita (co Author) for her support and valuable suggestions in the preparation of this chapter.

Dr. Ankita Pundir, would like to express my humble gratitude to Dr. Saurabh K Misra (the author) for giving me the opportunity to work on this chapter and for investing his belief in me. I hope I have done my part as per his expectations. I would also like to thank my beloved husband, Dr. Aakash Kumar Singh who is a budding rheumatologist, for his inputs and help in developing this chapter.

we also thank Marica Novakovic for being empathetic towards our personal aspects affecting the submission deadline of this chapter and for offering help all along.

Conflict of interest

“The authors declare no conflict of interest.”