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Mycoplasma genitalium is increasingly appreciated as a common cause of sexually transmitted disease syndromes, including urethritis in men and cervicitis, endometritis, pelvic inflammatory disease, and possibly preterm birth, tubal factor infertility, and ectopic pregnancy in women. Despite these disease associations, which parallel those of Chlamydia trachomatis and Neisseria gonorrhoeae, the mechanisms by which this pathogen elicits inflammation, causes cellular damage, and persists in its only natural host (humans) are unique and are not fully understood. The purpose of this review is to briefly provide a historical background on the discovery, microbiology, and recognition of M. genitalium as a pathogen, and then summarize the recent advances in our understanding of the molecular biology and pathogenesis of this unique urogenital organism. Collectively, the basic scientific discussions herein should provide a framework for understanding the clinical and epidemiological outcomes described in the accompanying articles in this supplemental issue.

Abstract First isolated in 1981, Mycoplasma genitalium is now well recognized as a frequent cause of urethritis and several other urogenital syndromes in both men and women. The cytoadhesins P110 (MgpC) and P140 (MgpB), located in the terminal organelle of the bacterium, mediate the establishment and persistence of M. genitalium infection in the reproductive tract tissues. This adhesion complex exposes a large extracellular domain, mediating bacterial adhesion to the anogenital tissue. The antigenic variation promoted by reciprocal recombination contribute to the efficient colonization of the urogenital environment and the immune evasion strategy of the bacterium. Although M. genitalium was traditionally detected in ano-genital samples, sexual transmission was not postulated until the early 2000s. Now, it is well accepted that M. genitalium can lead to a sexually transmitted infection. While vaginal sex may constitute the primary transmission route in terms of risk, anal intercourse in men who have sex with men is likely the most common cause of spread. Acknowledging the exquisite adaptation of the bacterium to diverse ecological niches in the human body, the unique features of the proteins P110 and P140 may influence transmission, dissemination and disease. Cytadhesins P110 and P140 are key for the pathogenesis and transmission of Mycoplasma genitalium infection

Mycoplasma genitalium is a sexually transmitted bacterial pathogen that infects men and women. Antigenic variation of MgpB and MgpC, the immunodominant adherence proteins of M. genitalium, is thought to contribute to immune evasion and chronic infection. We investigated the evolution of mgpB and mgpC sequences in men with non-gonococcal urethritis persistently infected with M. genitalium, including two men with anti-M. genitalium antibodies at enrollment and two that developed antibodies during follow-up. Each of the four patients was persistently infected with a different strain type and each patient produced antibodies targeting MgpB and MgpC. Amino acid sequence evolution in the variable regions of MgpB and MgpC occurred in all four patients with changes observed in single and multiple variable regions over time. Using the available crystal structure of MgpC of the G37 type strain we found that predicted conformational B cell epitopes localize predominantly to the variable region of MgpC, amino acids that changed during patient infection lie in these epitopes, and variant amino acids are in close proximity to the conserved sialic acid binding pocket. These findings support the hypothesis that sequence variation functions to avoid specific antibodies thereby contributing to persistence in the genital tract.

Mycoplasma genitalium is an emerging sexually transmitted pathogen implicated in urethritis in men and several inflammatory reproductive tract syndromes in women including cervicitis, pelvic inflammatory disease (PID), and infertility. This comprehensive review critically examines epidemiologic studies of M. genitalium infections in women with the goal of assessing the associations with reproductive tract disease and enhancing awareness of this emerging pathogen. Over 27,000 women from 48 published reports have been screened for M. genitalium urogenital infection in high- or low-risk populations worldwide with an overall prevalence of 7.3% and 2.0%, respectively. M. genitalium was present in the general population at rates between those of Chlamydia trachomatis and Neisseria gonorrhoeae. Considering more than 20 studies of lower tract inflammation, M. genitalium has been positively associated with urethritis, vaginal discharge, and microscopic signs of cervicitis and/or mucopurulent cervical discharge in seven of 14 studies. A consistent case definition of cervicitis is lacking and will be required for comprehensive understanding of these associations. Importantly, evidence for M. genitalium PID and infertility are quite convincing and indicate that a significant proportion of upper tract inflammation may be attributed to this elusive pathogen. Collectively, M. genitalium is highly prevalent in high- and low-risk populations, and should be considered an etiologic agent of select reproductive tract disease syndromes in women.

Mycoplasma genitalium and M. pneumoniae are two significant mycoplasmas that infect the urogenital and respiratory tracts of humans. Despite distinct tissue tropisms, they both have similar pathogenic mechanisms and infect/invade epithelial cells in the respective regions and persist within these cells. However, the pathogenic mechanisms of these species in terms of bacterium-host interactions are poorly understood. To gain insights on this, we infected HeLa cells independently with M. genitalium and M. pneumoniae and assessed gene expression by whole transcriptome sequencing (RNA-seq) approach. The results revealed that HeLa cells respond to M. genitalium and M. pneumoniae differently by regulating various protein-coding genes. Though there is a significant overlap between the genes regulated by these species, many of the differentially expressed genes were specific to each species. KEGG pathway and signaling network analyses revealed that the genes specific to M. genitalium are more related to cellular processes. In contrast, the genes specific to M. pneumoniae infection are correlated with immune response and inflammation, possibly suggesting that M. pneumoniae has some inherent ability to modulate host immune pathways.

Mycoplasma genitalium, the smallest prokaryotic microorganism capable of independent replication, is increasingly recognized as a sexually transmitted pathogen. M. genitalium protein of adhesion (MgPa) plays a pivotal role in the process of M. genitalium adhesion to host cells. We previously identified cyclophilin A as a cellular receptor of MgPa using the virus overlay protein binding assay (VOPBA) together with liquid chromatography-mass spectrometry (LC-MS). In the current study, we have evaluated H2B as an alternative cellular receptor for MgPa since H2B was assigned the second higher score as a potential binding partner of MgPa in the VOPBA and LC-MS screen. It was found that recombinant MgPa specifically bind to H2B both in the SV-HUC-1 cell membrane and in form of a recombinant protein. H2B was detected throughout the SV-HUC-1 cells, including the cytoplasmic membrane, cytosol and nucleus. Importantly, H2B partially inhibited the adhesion of M. genitalium to SV-HUC-1 cells. Finally, H2B was both co-precipitated with recombinant MgPa and co-localized with M. genitalium and recombinant MgPa in SV-HUC-1 cells. The above observations suggest that H2B may act as a potential cellular receptor of MgPa for mediating M. genitalium adhesion to host cells.

Background. The role of Mycoplasma genitalium in pelvic inflammatory disease is unclear. We conducted a cohort study to determine the prevalence and predictors of M. genitalium infection in female students, to explore its role in pelvic inflammatory disease and to estimate its annual incidence and persistence rate. Methods. Two thousand three hundred seventy-eight multiethnic, sexually active female students (mean age, 21 years) provided duplicate self-taken vaginal samples for a chlamydia screening trial. From this population, 2246 (94%) were followed up after 12 months and assessed for incidence of clinical pelvic inflammatory disease. In addition, 900 women (38%) returned follow-up samples via the postal service 11–32 months after recruitment. Stored samples were tested for M. genitalium. Results. The prevalence of M. genitalium at baseline was 3.3% (78 of 2378 women; 95% confidence interval [CI], 2.6%–4.1%). Infection was more common in women reporting ⩾2 sexual partners in the previous year, those with bacterial vaginosis, women aged <18 years, women of black ethnicity, and smokers. Multiple partners and bacterial vaginosis were independent risk factors for M. genitalium (adjusted risk ratio, 2.23 [95% CI, 1.39– 3.58] and 2.54 [95% CI, 1.61–4.01], respectively). The incidence of pelvic inflammatory disease over 12 months was 3.9% (3 of 77 women) among women with M. genitalium infection, compared with 1.7% (36 of 2169 women) among those without infection (risk ratio, 2.35; 95% CI, 0.74–7.46; P=.14). Annual incidence of M. genitalium infection in 873 women without M. genitalium infection at baseline who returned samples via the postal service was 0.9% (95% CI, 0.5%–1.6%). Seven (26%; 95% CI, 9%–43%) of 27 women with M. genitalium infection at baseline remained positive after 12–21 months; genotyping results suggest that these were persistent infections. Conclusions. M. genitalium infection is unlikely to be a major risk factor for clinical pelvic inflammatory disease in this population.

The impact of sexually transmitted infections (STI) on male fertility is controversial. Aims: To investigate the prevalence of urethritis-associated STIs (chlamydia, gonorrhoeae, Mycoplasma genitalium, trichomoniasis) among infertile males; to analyze the effect of STIs on semen parameters and blood PSA. Case-control study. Study group (n = 2000): males with fertility problems or desire for fertility check. Control group (n = 248): male partners of pregnant women. Analyses: polymerase chain reaction for STI, seminal interleukin 6 (IL-6), semen and fractionated urine, blood analyses (PSA, reproductive hormones). The prevalence of M. genitalium and chlamydia in the study group was 1.1% and 1.2%, respectively. The prevalence of chlamydia in the control group was 1.6%, while there were no M. genitalium cases. No cases with gonorrhoeae or trichomoniasis or combined infections were observed in neither group. There was a higher seminal concentration of neutrophils and IL-6 among M. genitalium positives compared with STI negatives. There was a trend toward a lower total count of spermatozoa and progressive motility among STI positives. No impact of STIs on PSA was found. The prevalence of STIs among infertile males is low. M. genitalium is associated with seminal inflammation. The impact of STIs on semen parameters deserves further investigations.

Information about the use of flow cytometry in the diagnosis of male urethritis is scarce. The current study aims to evaluate the performance of flow cytometry on first-voided urine in males with infectious urethritis (Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and Trichomonas vaginalis). Male patients of the Andrology Centre (Tartu University Hospital, Estonia) were recruited during the period March 2015 -January 2018. Cases included 306 patients with infectious urethritis caused by Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and/or Trichomonas vaginalis. The control group consisted of 192 patients without uro-genital complaints, negative tests for C. trachomatis, N. gonorrhoeae, M. genitalium and T. vaginalis from first-voided urine and no inflammation in first-voided urine, mid-stream urine and urine after prostate massage. C. trachomatis, N. gonorrhoeae, M. genitalium and T. vaginalis were detected from first-voided urine using polymerase chain reaction (PCR) method. First-voided urine was analysed using urine particle analyzer Sysmex UF-500i. The most prevalent infection was chlamydia (64.1%), followed by Mycoplasma genitalium (20.9%), gonorrhoea (7.8%) and trichomoniasis (1.6%). Gonorrhoea caused the highest flow-cytometric leucocyte/bacteria count, followed by chlamydia and Mycoplasma genitalium. Trichomonas vaginalis showed nearly absent inflammation in first-voided urine. Using an empiric flow-cytometry diagnostic threshold for urethritis in first-voided urine (leucocytes ≥ 15/μl and bacteria ≥ 20/μl) the total calculated sensitivity was over 90%. However, when applying such criteria for deciding whether to perform first-voided urine PCR for C. trachomatis, N. gonorrhoeae, M. genitalium and T. vaginalis or not, we could miss 23 cases with infectious urethritis that makes up 7,5% of all proven cases. Flow cytometry of first-voided urine can be considered as a rapid and objective screening method in case of suspected male infectious urethritis.

ObjectivesThis investigation sought to characterise risk factors associated with acquisition of traditional and emerging agents of sexually transmitted infection (STI) in a cohort of young men who have sex with men and transgender women.Methods917 participants provided urine and rectal swab submissions assessed by transcription-mediated amplification (TMA)-based assays for Chlamydia trachomatis and Neisseria gonorrhoeae and by off-label TMA-based Trichomonas vaginalis and Mycoplasma genitalium testing. A subset provided specimens at 6-month and 12-month follow-up visits.ResultsPrevalence of M. genitalium from rectal and urine specimens (21.7% and 8.9%, respectively) exceeded that of C. trachomatis (8.8% and 1.6%) and other STI agents. Black participants yielded higher prevalence of M. genitalium (30.6%) than non-black participants (17.0%; χ²=22.39; p<0.0001). M. genitalium prevalence from rectal specimens was 41.5% in HIV-positive participants vs 16.3% in HIV-negative participants (χ²=57.72; p<0.0001). Participant age, gender identity, condomless insertive anal/vaginal sexual practice and condomless receptive anal sexual practice were not associated with rectal C. trachomatis (p≥0.10), N. gonorrhoeae (p≥0.29), T. vaginalis (p≥0.18) or M. genitalium (p≥0.20) detection. While prevalence of T. vaginalis was calculated at ≤1.0%, baseline rectal and urine screening status was predictive of detection/non-detection at follow-up. A non-reactive M. genitalium baseline rectal or urine screening result was less predictive of non-reactive follow-up versus C. trachomatis, N. gonorrhoeae and T. vaginalis.ConclusionsRectal M. genitalium detection is associated with black race and HIV seropositivity. Baseline M. genitalium infection influences subsequent detection of the organism.