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Mycoplasma genitalium, Ureaplasma urealyticum and Mycoplasma hominis are bacterial pathogens found in the genitourinary tract, implicated in a range of infections. In women, these infections including pelvic inflammatory disease, vaginitis, infertility, and cervical cancer, while in men, they can cause non-gonococcal urethritis, prostate cancer, among other conditions. These infections are a global health concern, with China identified as a country with a high prevalence. This review provides a comprehensive overview of the epidemiology, causative factors, and diagnostic methods for these three Mycoplasma species with in China. The rise of multi-drug resistance, driven by antibiotics overuse, poses a significant challenge to treatment, complicating patient management. These Mycoplasma species employ unique adhesion mechanisms that trigger a cascade of signal transduction, culminating to inflammatory responses, tissue damage, and the release of toxic metabolites. Here, we delineate the mechanisms of underlying Mycoplasma resistance and propose key therapeutic strategies for these three mycoplasmas in China. This includes a summary of effective antibiotic treatment strategies, and potential combinations of therapeutic to improve cure rates, and a discussion of potential therapeutic approaches using traditional Chinese medicine.

Mycoplasma hominis is an opportunistic human mycoplasma. Two other pathogenic human species, M. genitalium and Ureaplasma parvum, reside within the same natural niche as M. hominis: the urogenital tract. These three species have overlapping, but distinct, pathogenic roles. They have minimal genomes and, thus, reduced metabolic capabilities characterized by distinct energy-generating pathways. Analysis of the M. hominis PG21 genome sequence revealed that it is the second smallest genome among self-replicating free living organisms (665,445 bp, 537 coding sequences (CDSs)). Five clusters of genes were predicted to have undergone horizontal gene transfer (HGT) between M. hominis and the phylogenetically distant U. parvum species. We reconstructed M. hominis metabolic pathways from the predicted genes, with particular emphasis on energy-generating pathways. The Embden-Meyerhoff-Parnas pathway was incomplete, with a single enzyme absent. We identified the three proteins constituting the arginine dihydrolase pathway. This pathway was found essential to promote growth in vivo. The predicted presence of dimethylarginine dimethylaminohydrolase suggested that arginine catabolism is more complex than initially described. This enzyme may have been acquired by HGT from non-mollicute bacteria. Comparison of the three minimal mollicute genomes showed that 247 CDSs were common to all three genomes, whereas 220 CDSs were specific to M. hominis, 172 CDSs were specific to M. genitalium, and 280 CDSs were specific to U. parvum. Within these species-specific genes, two major sets of genes could be identified: one including genes involved in various energy-generating pathways, depending on the energy source used (glucose, urea, or arginine) and another involved in cytadherence and virulence. Therefore, a minimal mycoplasma cell, not including cytadherence and virulence-related genes, could be envisaged containing a core genome (247 genes), plus a set of genes required for providing energy. For M. hominis, this set would include 247+9 genes, resulting in a theoretical minimal genome of 256 genes.

Restriction-modification (RM) systems are widespread defense mechanisms in prokaryotes that protect the host from potentially harmful foreign DNA. They typically consist of a DNA methyltransferase (MTase), which methylates the host genome at an adenine (6 mA methylation) or cytosine (4mC or 5mC), and a restriction endonuclease (REase), which cleaves foreign, unmethylated DNA. In addition to the 2023 published family of 5mC-MTases, an Hga I-homolog RM system was detected in Mycoplasma hominis with the more rare constellation of two 5mC MTase genes, called RM. Mho VI. A qPCR screening of 239 randomly selected M. hominis isolates revealed a prevalence of the Mho VI-RM system of 12.97% ( n  = 31/239). Notably, in all tested Mho VI-positive isolates, the Mho VI-RM cassette localized between MHO_3110 and MHO_3120 and comprised an XRE-family transcriptional regulator gene in addition to the RM genes. Intra-species conservation of the encoded Mho VI-enzymes was high (> 99% identities), and inter-species conservation was the lowest compared to the eponymous species Haemophilus gallinarum (46.6% M1. Mho VI; 48.1% M2. Mho VI; 27.4% R. Mho VI). A polycistronic organization of the Mho VI-genes was strongly suspected due to the discovery of gene-overlapping mRNA regions. The MTases activity was demonstrated in RM. Mho VI positive M. hominis isolates by protection of genomic DNA from cleavage by the methylation-sensitive endonuclease Hga I; and bioinformatics analysis using the Dorado basecaller on the Oxford Nanopore sequenced genomes revealed methylation rates of the respective motifs, 5’-GA m CGC-3’/5’-G m CGTC-3’, above 95% in Mho VI-positives, with a higher methylation frequency of 5’-GA m CGC-3’ than 5’-G m CGTC-3 in most isolates. A final proof of Mho VI-RM representing an Hga I-RM-like methylation activity was demonstrated through expression and analysis of recombinant rM2. Mho VI in E. coli .

T. vaginalis and M. hominis form a unique case of endosymbiosis that modulates the parasite’s pathobiology. Recently, a new nonculturable mycoplasma species (“ Candidatus Mycoplasma girerdii”) has been described as closely associated with the protozoon. Trichomonas vaginalis can host the endosymbiont Mycoplasma hominis , an opportunistic pathogenic bacterium capable of modulating T. vaginalis pathobiology. Recently, a new noncultivable mycoplasma, “ Candidatus Mycoplasma girerdii,” has been shown to be closely associated with women affected by trichomoniasis, suggesting a biological association. Although several features of “ Ca. M. girerdii” have been investigated through genomic analysis, the nature of the potential T. vaginalis -“ Ca. M. girerdii” consortium and its impact on the biology and pathogenesis of both microorganisms have not yet been explored. Here, we investigate the association between “ Ca. M. girerdii” and T. vaginalis isolated from patients affected by trichomoniasis, demonstrating their intracellular localization. By using an in vitro model system based on single- and double- Mycoplasma infection of Mycoplasma -free isogenic T. vaginalis , we investigated the ability of the protist to establish a relationship with the bacteria and impact T. vaginalis growth. Our data indicate likely competition between M. hominis and “ Ca. M. girerdii” while infecting trichomonad cells. Comparative dual-transcriptomics data showed major shifts in parasite gene expression in response to the presence of Mycoplasma , including genes associated with energy metabolism and pathogenesis. Consistent with the transcriptomics data, both parasite-mediated hemolysis and binding to host epithelial cells were significantly upregulated in the presence of either Mycoplasma species. Taken together, these results support a model in which this microbial association could modulate the virulence of T. vaginalis . IMPORTANCE T. vaginalis and M. hominis form a unique case of endosymbiosis that modulates the parasite’s pathobiology. Recently, a new nonculturable mycoplasma species (“ Candidatus Mycoplasma girerdii”) has been described as closely associated with the protozoon. Here, we report the characterization of this endosymbiotic relationship. Clinical isolates of the parasite demonstrate that mycoplasmas are common among trichomoniasis patients. The relationships are studied by devising an in vitro system of single and/or double infections in isogenic protozoan recipients. Comparative growth experiments and transcriptomics data demonstrate that the composition of different microbial consortia influences the growth of the parasite and significantly modulates its transcriptomic profile, including metabolic enzymes and virulence genes such as adhesins and pore-forming proteins. The data on modulation from RNA sequencing (RNA-Seq) correlated closely with those of the cytopathic effect and adhesion to human target cells. We propose the hypothesis that the presence and the quantitative ratios of endosymbionts may contribute to modulating protozoan virulence. Our data highlight the importance of considering pathogenic entities as microbial ecosystems, reinforcing the importance of the development of integrated diagnostic and therapeutic strategies.

Background. The prevalence of Trichomonas vaginalis infection is highest in women with intermediate Nugent scores. We hypothesized that the vaginal microbiota in T. vaginalis—infected women differs from that in T. vaginalis—uninfected women. Methods. Vaginal samples from 30 T. vaginalis—infected women were matched by Nugent score to those from 30 T. vaginalis—uninfected women. Equal numbers of women with Nugent scores categorized as normal, intermediate, and bacterial vaginosis were included. The vaginal microbiota was assessed using 454 pyrosequencing analysis of polymerase chain reaction—amplified 16S ribosomal RNA gene sequences. The 16S ribosomal RNA gene sequence of an unknown organism was obtained by universal bacterial polymerase chain reaction amplification, cloning, and sequencing. Results. Principal coordinates analysis of the pyrosequencing data showed divergence of the vaginal microbiota in T. vaginalis—infected and T. vaginalis—uninfected patients among women with normal and those with intermediate Nugent scores but not among women with bacterial vaginosis. Cluster analysis revealed 2 unique groups of T. vaginalis—infected women. One had high abundance of Mycoplasma hominis and other had high abundance of an unknown Mycoplasma species. Women in the former group had clinical evidence of enhanced vaginal inflammation. Conclusions. T. vaginalis may alter the vaginal microbiota in a manner that is favorable to its survival and/or transmissibility. An unknown Mycoplasma species plays a role in some of these transformations. In other cases, these changes may result in a heightened host inflammatory response.

Introduction: Mycoplasma hominis (M. hominis) is a commensal that mainly colonizes in the microflora of the genitourinary tracts and is associated with urogenital tract infections. There are reports of central nervous system (CNS) infections in neonates caused by M. hominis. Nevertheless, M. hominis CNS infections in non-neonatal patients are extremely rare. Herein, we have reported a case of a man who suffered from intracranial infection secondary to M. hominis after neurosurgical operation. Additionally, we reviewed the relevant published literature to raise awareness on such infections and highlight the importance of proper treatments. Case presentation: A 68-year-old man underwent emergence craniotomy for intracerebellar hemorrhage. He presented with a moderate fever unresponsive to piperacillin-tazobactam on the seventh day after the surgery. His body temperature continued to increase, and he presented with signs of CNS infection. The antimicrobial therapy was switched to meropenem and vancomycin. No obvious reduction in the body temperature was observed. The cerebrospinal fluid (CSF) obtained previously revealed tiny point colonies which were morphologically consistent with M. hominis and subsequently confirmed by metagenomic next-generation sequencing (mNGS). Thus, M. hominis induced intracranial infection was diagnosed, and a combination therapy with moxifloxacin and minocycline was implemented. Fortunately, the patient’s body temperature decreased to normal range after effective antibiotic therapy. Conclusions: Based on the lesson of our case and a thorough review of published literature, the possibility of M. hominis induced CNS infections after neurosurgical intervention should not be ignored, especially when there is no response to standard antimicrobial therapy.

In Mycoplasma hominis, two genes (alr and goiB) have been found to be associated with the invasion of the amniotic cavity, and a single gene (goiC) to be associated with intra-amniotic infections and a high risk of preterm birth. The syntopic presence of Ureaplasma spp. in the same patient has been shown to correlate with the absence of goiC in M. hominis. The aim of our study was to investigate the presence of alr, goiB, and goiC genes in two groups of M. hominis isolates collected from symptomatic and asymptomatic male and non-pregnant female patients attending an Outpatients Centre. Group A consisted of 26 isolates from patients with only M. hominis confirmed; group B consisted of 24 isolates from patients with Ureaplasma spp. as the only co-infection. We extracted DNA from all M. hominis isolates and analysed the samples for the presence of alr, goiB, and goiC in a qPCR assay. Additionally, we determined their cytotoxicity against HeLa cells. We confirmed the presence of the alr gene in 85% of group A isolates and in 100% of group B isolates; goiB was detected in 46% of the samples in both groups, whereas goiC was found in 73% of group A and 79% of group B isolates, respectively. It was shown that co-colonisation with Ureaplasma spp. in the same patient had no effect on the presence of goiC in the respective M. hominis isolate. We did not observe any cytotoxic effect of the investigated isolates on human cells, regardless of the presence or absence of the investigated genes.

Introduction: Trichomonas vaginalis (TV) is the etiological agent of the common non-viral sexually transmitted infection (STI), trichomoniasis. TV can inherently harbour Mycoplasma hominis and Trichomonas vaginalis virus (TVV) species. Endosymbiosis of TV with M. hominis and TVV may contribute to metronidazole resistance in this pathogen. This study determined the prevalence of TVVs across clinical isolates of TV, as well as the symbiosis between TV, TVV, and M. hominis in relation to metronidazole resistance. Methodology: Twenty-one clinical isolates of TV were analysed in this study. The isolates were subjected to drug susceptibility assays using varying concentrations of metronidazole. Nucleic acids (RNA and DNA) were extracted from the isolates for molecular assays. The presence of intracellular M. hominis was determined by 16S rRNA polymerase chain reaction (PCR) with specific primers. The presence of the individual TVVs was determined by PCR using gene specific primers with template cDNA. Results: The prevalence of TVV and M. hominis were 76% (16/21) and 86% (18/21), respectively. No significant associations were observed between the presence of TVV and clinical symptoms. A significant association was noted between the coinfection of TVV4 and M. hominis (p = 0.014). The presence of any TVV was significantly associated with metronidazole susceptibility patterns (p = 0.012). No significant associations were noted between the coinfection of endosymbionts and metronidazole resistance. Conclusions: The information obtained displays the ability of TV to form an endosymbiotic relationship with several microorganisms, simultaneously. Based on these findings, both endosymbionts pose no significant influence on metronidazole resistance.

Background. Bacterial vaginosis is a risk factor for preterm birth. The various conventional methods for its diagnosis are laborious and not easily reproducible. Molecular quantification methods have been reported recently, but the specific risk factors they might identify remain unclear. Methods. A prospective multicenter national study included pregnant women at risk of preterm birth. A quantitative molecular tool using a specific real-time polymerase chain reaction assay and serial dilutions of a plasmid suspension quantified Atopobium vaginae, Gardneralla vaginalis, loctobacilli, Mycoplasma hominis, and the human albumin gene (for quality control). Results. In 813 pregnancies, high vaginal loads of either or both of A. vaginae and G. vaginalis were associated with preterm birth (hazard ratio [HR], 3.9; 95% confidence interval {CI}, 1.1–14.1; P = .031). A high vaginal load of A. vaginae was significantly associated with shortened time to delivery and therefore pregnancy length. These times were, respectively, 152.2 and 188.2 days (HR, 5.6; 95% CI, 1.5–21.3; P< .001) before 22 weeks, 149.0 and 183.2 days (HR, 2.8; 95% CI, 1.1–8.2; P = .048) before 28 weeks, and 132.6 and 170.4 days (HR, 2.2; 95% CI, 1.1–4.6; P = .033) before 32 weeks. After multivariate analysis, A. vaginae levels ≥108 copies/mL remained significantly associated with delivery before 22 weeks of gestation (adjusted HR, 4.7; 95% CI, .2–17.6; P = .014). Conclusions. High vaginal loads of A. vaginae and G. vaginalis are associated with late miscarriage and prematurity in high-risk pregnancies. A high vaginal load of A. vaginae (DNA level ≥108 copies/mL) identifies a population at high risk of preterm birth. Further studies that both screen for and then treat A. vaginae are needed. Clinical Trials Registration. NCT00484653.

Background. Bacterial vaginosis (BV) is a poorly detected public health problem that is associated with preterm delivery and for which no reliable diagnostic tool exists. Methods. Molecular analysis of 231 vaginal samples, classified by Gram stain–based Nugent score, was used to propose molecular criteria for BV; these criteria were prospectively applied to 56 new samples. A quantitative molecular tool targeting 8 BV-related microorganisms and a human gene was developed using a specific real-time polymerase chain reaction assay and serial dilutions of a plasmid suspension. The targeted microorganisms were Gardnerella vaginalis, Lactobacillus species, Mobiluncus curtisii, Mobiluncus mulieris, and Candida albicans (which can be identified by Gram staining), as well as Atopobium vaginae, Mycoplasma hominis, and Ureaplasma urealyticum (which cannot be detected by Gram staining). Results. With use of the Nugent score, 167 samples were classified as normal, 20 were classified as BV, and 44 were classified as intermediate. Except for U. urealyticum, M. mulieris, and Lactobacillus species, DNA of the tested bacteria was detected more frequently in samples demonstrating BV, but the predictive value of such detection was low. The molecular quantification of A. vaginae (DNA level, ⩾108 copies/mL) and G. vaginalis (DNA level, ⩾109 copies/mL) had the highest predictive value for the diagnosis of BV, with excellent sensitivity (95%), specificity (99%), and positive (95%) and negative (99%) predictive values; 25 (57%) of the samples demonstrating intermediate flora had a BV profile. When applied prospectively, our molecular criteria had total positive and negative predictive values of 96% and 99%, respectively. Conclusions. We report a highly reproducible, quantitative tool to objectively analyze vaginal flora that uses cutoff values for the concentrations of A. vaginae and G. vaginalis to establish the molecular diagnosis of BV.