Endocervical Epithelium Research Articles

Mullerianosis of the urinary bladder: A great mimicker

Mullerianosis is a rare benign lesion consisting of an admixture of two or more of the following tissues: endometriosis, endocervicosis, and endosalpingiosis. It most commonly affects the urinary bladder and females of reproductive age group. Müllerianosis of the bladder is an extremely rare entity with fewer than 30 cases reported. Herein we report one such rare case of mullerianosis of the urinary bladder in a 33-year-old female who had undergone cesarian section 2 years back, presented with painless hematuria associated with menstruation. USG revealed a soft tissue lesion measuring 23×11 mm abutting the wall of the urinary bladder and extending into it. These findings were suspicious for endometriosis. The patient was admitted to the hospital for transurethral resection of a bladder lesion (TURBT). Operative findings revealed a solid 2x2 cm mass in the posterior wall of the urinary bladder. Superficial and deep TURBT chips were sent for histopathological examination. On microscopic examination, there were variable-sized glands lined by endometrial, endocervical, or tubal epithelium embedded in the bladder wall. The case was diagnosed as mullerianosis of the urinary bladder. As this rare entity, since it mimics benign and malignant neoplasms clinically and radiologically, pathologists should be aware of this rare entity to avoid misdiagnosis, which has great therapeutic implications for the patient.

888 Vaginal progesterone effects at the endocervical epithelium in cell culture and preterm birth mouse model

888 Vaginal progesterone effects at the endocervical epithelium in cell culture and preterm birth mouse model

Inhibition of cytosine 5-hydroxymethylation during progression of cancer precursor lesions in the uterine cervix.

Methylation and hydroxymethylation of cytosine moieties in CpG islands of specific genes are epigenetic processes shown to be involved in the development of cervical (pre)neoplastic lesions. We studied global (hydroxy)methylation during the subsequent steps in the carcinogenic process of the uterine cervix by using immunohistochemical protocols for the detection of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in paraffin-embedded tissues of the normal epithelia and (pre)malignant lesions. This approach allowed obtaining spatially resolved information of (epi)genetic alterations for individual cell populations in morphologically heterogeneous tissue samples. The normal ectocervical squamous epithelium showed a high degree of heterogeneity for both modifications, with a major positivity for 5-mC in the basal and parabasal layers in the ectocervical region, while 5-hmC immunostaining was even more restricted to the cells in the basal layer. Immature squamous metaplasia, characterized by expression of SOX17, surprisingly showed a decrease of 5-hmC in the basal compartments and an increase in the more superficial layers of the epithelium. The normal endocervical glandular epithelium showed a strong immunostaining reactivity for both modifications. At the squamocolumnar junctions, a specific 5-hmC pattern was observed in the squamous epithelium, resembling that of metaplasia, with the typical weak to negative reaction for 5-hmC in the basal cell compartment. The reserve cells underlying the glandular epithelium were also largely negative for 5-hmC but showed immunostaining for 5-mC. While the overall methylation status remained relatively constant, about 20% of the high-grade squamous lesions showed a very low immunostaining reactivity for 5-hmC. The (pre)malignant glandular lesions, including adenocarcinoma in situ (AIS) and adenocarcinoma showed a progressive decrease of hydroxymethylation with advancement of the lesion, resulting in cases with regions that were negative for 5-hmC immunostaining. These data indicate that inhibition of demethylation, which normally follows cytosine hydroxymethylation, is an important epigenetic switch in the development of cervical cancer.

Assessing the diagnostic value of CAIX and ProEx-C in cervical squamous intraepithelial lesions

Cervical squamous intraepithelial lesions (SILs) may present a diagnostic challenge due to their morphological similarity to benign conditions and variability in interpretation, necessitating the exploration of objective biomarkers to aid in their identification and grading. This study evaluates the immunohistochemical markers Carbonic Anhydrase IX (CAIX) and ProEx-C to assess their diagnostic potential in cervical SILs. We retrospectively identified 56 SIL cases, including 20 low-grade SILs (LSIL) and 36 high-grade SILs (HSIL), alongside a control group of nine chronic cervicitis cases. Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissue blocks, and the sensitivity and specificity of CAIX and ProEx-C were evaluated for detecting and grading SILs. CAIX exhibited a sensitivity of 64.3 % and a specificity of 100 % for detecting SILs. ProEx-C staining displayed a sensitivity of 66.1 % and a specificity of 100 % for detecting SILs. The combination of CAIX and ProEx-C staining increased the sensitivity for detecting SILs to 80.4 % without compromising the specificity. These markers alone or in combination were not found to be significant in distinguishing LSIL from HSIL. Both markers showed positivity in benign endocervical and squamous epithelium in high rates. In conclusion, CAIX and ProEx-C are valuable immunohistochemical markers for detecting SILs in cervical specimens, with high sensitivity and specificity. Further research is needed to elucidate their roles in cervical carcinogenesis and their relationship with HPV infection.

The Autogenous Coelenterate-Endocervical Polyp Uterine Cervix

Endocervical polyp represents as a benign, exophytic lesion constituted of variable admixture of proliferating endocervical glandular epithelium and metaplastic squamous epithelium permeated with a fibro-vascular core. The commonly encountered endocervical polyp is frequently accompanied by chronic inflammation, erosion of superficial epithelial surface and reactive alterations of layering epithelium.

Inmixed and Bellicose-Adenosquamous Carcinoma-Uterine Cervix

Adenosquamous carcinoma of uterine cervix is a preponderantly high grade neoplasm configured of admixed glandular articulations and squamous epithelium wherein glassy cell carcinoma emerges as an exceptional, aggressive variant. Adenosquamous carcinoma is posited to arise from sub-columnar reserve cells confined to endocervical basal epithelium. Cytological smears depict papillary articulations admixed with bland columnar epithelial cells and high grade squamous intraepithelial lesion. The biphasic tumour is composed of well defined, malignant components of glandular articulations and poorly differentiated squamous epithelium. Glassy cell carcinoma demonstrates solid cell nests comprised of pleomorphic, polygonal tumour cells pervaded with glassy, eosinophilic cytoplasm, enlarged, eosinophilic nuclei, prominent nucleoli and distinct cytoplasmic membrane. Neoplastic cells appear enmeshed within an intense inflammatory cell infiltrate with significant eosinophils. Glassy cell carcinoma appears immune reactive to MUC1, MUC2, epithelial membrane antigen (EMA), CAM5.2 or p63 with focal immune reactivity to carcinoembryonic antigen (CEA). Adenosquamous carcinoma requires segregation from neoplasms such as adenocarcinoma with coexisting squamous intraepithelial lesion (SIL), adenoid basal carcinoma, cervical extension of endometrial adenocarcinoma, and squamous cell carcinoma with focal mucin droplets, large cell non keratinizing squamous cell carcinoma or lymphoepithelioma-like carcinoma. Tumefaction may be appropriately treated by radical abdominal hysterectomy followed by adjuvant chemotherapy and radiation therapy.

Role of kshara (an alkali preparation) in wound healing with special reference to cervical erosion

Cervical erosion is caused by the replacement of the stratified squamous epithelium of the ectocervix with the endocervical columnar epithelium. In Ayurvedic classics, it can be co-related to garbhashayagrivagatavrana. Its management mainly includes destruction of overgrown epithelium by different techniques has its own limitations and side effects. Further observing its prevalence there is a requirement for a treatment modality which is more efficient and cost-effective. Kshara which possesses lekhana (scrapping), vrana-shodhana (wound cleansing), and ropana (wound healing) properties as described in Ayurveda, provides a scientific background of the therapeutic application in the management. Different review works revealed the potential use of kshara on wound healing due to its alkalinity which maintain the body pH within the normal range and thus maintains different cellular and extracellular function. Therefore, kshara is found to be an important preparation that has been investigated for its gynecological uses by different scholars.

Pap Smear Collection and Preparation: Key Points

Cytology is the science of study of cells. It is derived from the Greek word “cytos” which means cells. The cells of the cervicovaginal epithelium are continuously evolving. The mature cells reach the surface and are then exfoliated. Initially, these exfoliated cells were collected from the posterior fornix, which showed cells from endocervix, ectocervix, and the vaginal epithelium. Hence, it was known as the exfoliative vaginal cytology. But now, the cells are taken directly by scraping the ecto and the endocervix. A variety of sampling devices are available in the market. The basic aim is to augment sampling of the complete transformation zone (TZ) as well as the squamocolumnar junction (SCJ) and cause least possible trauma to the cervical and endocervical epithelium during its use. The SCJ is of crucial significance for cervical cancer pathogenesis. Most of the precancerous changes take place within the TZ and at the SCJ. Hence, the collection of cells from this area is of utmost importance. The reliability of cervical cytology for the detection of precancerous lesions also strongly depends on immediate wet fixation of the smear. Therefore, the gynecologists or the paramedics who perform the conventional Pap smears must not only be trained in the art of cell collection and smearing of the material onto the glass slides but also learn immediate wet fixation of the cervical cells. Liquid-based preparations have made all these steps relatively easy for them as the design of the Cervex brush is such that it mostly ensures the sampling of the complete TZ and the SCJ. Pre-fixation of cells occurs in the vial containing a weak fixative and the transfer of cells onto the glass slide is standardized by the automated stations designed for this purpose. This chapter gives an in depth description of the prerequisites and precautions while collecting and preparing a Pap smear with different devices, especially for settings where conventional smears are still the norm. Instructions for women undergoing Pap smear and the medical personnel who conduct this test are also highlighted.

Nonneoplastic Cervical Cytology.

Diagnostic cytology of cervix can be made strong if normal cytology is known thoroughly. Cervical lining comprises three layers of squamous cells, the basal, intermediate, and superficial cells. Knowing the dimensions of these cells, especially the intermediate cells, helps to diagnose the squamous intraepithelial lesions accurately. Furthermore, recognizing the parabasal cells in the menopausal smears, either singly or as syncytial aggregates, is important to avoid overdiagnosis of squamous intraepithelial lesions. The other cell type in the cervical lining is the endocervical glandular epithelium. Exfoliated endocervical cells may at times resemble endometrial glandular cells. The morphology and differences between these two cell types have been highlighted. It is essential to recognize and report endometrial cells in women of 40 years and above according to the recent Bethesda System for Reporting Cervical Cytology. The squamous epithelium of cervix and vagina is highly sensitive to estrogen and progesterone hormones. Hence, the Pap smears, if desired, can help in evaluating the hormonal status of the woman. The ratio of parabasal, intermediate, and superficial squamous cells can help in calculating various maturation indices.

Tumor board presentation of a woman with metastatic, hormone receptor‐positive, mismatch repair‐deficient endometrial cancer

Tumor board presentation of a woman with metastatic, hormone receptor‐positive, mismatch repair‐deficient endometrial cancer

Gonococcal invasion into epithelial cells depends on both cell polarity and ezrin.

Neisseria gonorrhoeae (GC) establishes infection in women from the cervix, lined with heterogeneous epithelial cells from non-polarized stratified at the ectocervix to polarized columnar at the endocervix. We have previously shown that GC differentially colonize and transmigrate across the ecto and endocervical epithelia. However, whether and how GC invade into heterogeneous cervical epithelial cells is unknown. This study examined GC entry of epithelial cells with various properties, using human cervical tissue explant and non-polarized/polarized epithelial cell line models. While adhering to non-polarized and polarized epithelial cells at similar levels, GC invaded into non-polarized more efficiently than polarized epithelial cells. The enhanced GC invasion in non-polarized epithelial cells was associated with increased ezrin phosphorylation, F-actin and ezrin recruitment to GC adherent sites, and the elongation of GC-associated microvilli. Inhibition of ezrin phosphorylation inhibited F-actin and ezrin recruitment and microvilli elongation, leading to a reduction in GC invasion. The reduced GC invasion in polarized epithelial cells was associated with non-muscle myosin II-mediated F-actin disassembly and microvilli denudation at GC adherence sites. Surprisingly, intraepithelial GC were only detected inside epithelial cells shedding from the cervix by immunofluorescence microscopy, but not significantly in the ectocervical and the endocervical regions. We observed similar ezrin and F-actin recruitment in exfoliated cervical epithelial cells but not in those that remained in the ectocervical epithelium, as the luminal layer of ectocervical epithelial cells expressed ten-fold lower levels of ezrin than those beneath. However, GC inoculation induced F-actin reduction and myosin recruitment in the endocervix, similar to what was seen in polarized epithelial cells. Collectively, our results suggest that while GC invade non-polarized epithelial cells through ezrin-driven microvilli elongation, the apical polarization of ezrin and F-actin inhibits GC entry into polarized epithelial cells.

PROBLEMATIC ISSUES IN THE EVALUATION OF MOLECULAR CHARACTERISTICS AND POTENTIAL NEOPLASTIC TRANSFORMATION OF CERVICAL METAPLASIA

Metaplasia represents the replacement of one differentiated cell type with another differentiated cell type, which is frequently seen in uterine cervix, particularly in endocervical epithelium. There are many different types of metaplasia in endocervix. It is suggested that metaplasia represents the fertile soil for the development of neoplasia. However, which cases of metaplasia transform into neoplasia, which type of metaplasia is more realted to neoplastic transformation or if there are some molecular markers which can predict the potential of neoplastic transformation, are nowadays less known. Current review represents the critical discussion of the available literature with regards to the evaluation of molecular markers and the potential of neoplastic transformation in cervical metaplasia.

Cervical Precancers Originate From Infected Proliferating Reserve Cells: A Comparative Histologic and Genetic Study of Thin and Thick High-grade Squamous Intraepithelial Lesions.

Human papillomavirus (HPV)-induced invasive cervical squamous cell cancer (SCC) develop via high-grade squamous intraepithelial lesion (HSIL). In contrast to classic thick HSIL, thin HSIL (≤9 cell layers) are poorly documented. This study compares histology, HPV genotypes, and aberrations in 50 cancer genes of 45 thin HSIL to 45 thick HSIL, 20 pT1a SCC, and 40 ≥pT1b SCC. Thin HSIL arose from proliferating reserve cells within endocervical epithelium or immature metaplasia throughout the transformation zone after infection with high-risk HPV genotypes (36/45; 80%), and 20% non-high-risk HPV genotypes compared with 2.5% thick HSIL, pT1a SCC, and ≥pT1b SCC. Thin HSIL were multifocal proliferations with varying epithelial thickness between 1 and 2 to 9 cell layers, with occasional transitions to thick HSIL or concomitant lesions of thick HSIL. Overall, 40% thin HSIL were located distant to and most thick HSIL occurred near or at the squamocolumnar junction. Only 20% thick HSIL showed koilocytosis. All HSIL lacked somatic gene mutations, compared with 30% pT1a and 55%≥pT1b SCC. Overrepresented rare germline variants in the MET, JAK3, and FGFR3 genes occurred in all patient groups. In summary, thin and thick HSIL arose independently of somatic gene mutations. The maturation level of the squamous epithelium at the time of transforming infection determines if a thick HSIL develops directly from HPV-infected proliferating reserve cells via thin HSIL or in stratified glycogenated squamous epithelium via low-grade squamous intraepithelial lesion. These observations raise doubts about the biological relevance of separation into thin and thick HSIL. The oncogenic potential of HPV genotypes but also germline variants may influence the natural history.

Patient-derived organoids model cervical tissue dynamics and viral oncogenesis in cervical cancer.

Cervical cancer is a common gynecological malignancy often caused by high-risk human papillomavirus. There is a paucity of human-derived culture systems to study the cervical epithelium and the cancers derived thereof. Here we describe a long-term culturing protocol for ecto- and endocervical epithelia that generates 3D organoids that stably recapitulate the two tissues of origin. As evidenced for HSV-1, organoid-based cervical models may serve to study sexually transmitted infections. Starting from Pap brush material, a small biobank of tumoroids derived from affected individuals was established that retained the causative human papillomavirus (HPV) genomes. One of these uniquely carried the poorly characterized HPV30 subtype, implying a potential role in carcinogenesis. The tumoroids displayed differential responses to common chemotherapeutic agents and grew as xenografts in mice. This study describes an experimental platform for cervical (cancer) research and for future personalized medicine approaches.

Noninvasive, in vivo assessment of the cervical microcirculation using incident dark field imaging

AimThis study evaluates the feasibility of handheld vital microscopy for noninvasive, objective assessment of the microcirculation of the human uterine cervix. We qualitatively and quantitatively describe the microcirculation in healthy subjects in order to provide a basis for its application in cervical pathology. MethodsIncident dark field imaging was used to image the microcirculation in four quadrants of the uterine ectocervix in ten healthy participants. If the squamocolumnar junction was visible, measurements were repeated on the endocervical columnar epithelium as well. Image acquisition time was recorded and participants scored the experienced level of discomfort. Angioarchitecture was classified according to Weber's classification. Quantitative parameters included capillary density (CD), total and perfused vessel density (TVD, PVD), proportion of perfused vessels (PPV) and microvascular flow index (MFI). ResultsImage acquisition was easy, fast and well tolerated. Angioarchitecture was characterized by two distinctive and organized patterns; capillary loops underneath the squamous epithelium of the ectocervix and vascular networks underneath the columnar epithelium. In the image sequences containing capillary loops, mean CD was 33.2 cpll/mm2 (95% CI 28.2–38.2 cpll/mm2). In the image sequences with vascular networks, mean TVD was 12.5 mm/mm2 (95% CI 11.2–13.77 mm/mm2), mean PVD was 12.2 (95% CI 11.0–13.5 mm/mm2), MFI was 3 and PPV was 100%. ConclusionsIncident dark field imaging allows for noninvasive, real time visualization and objective evaluation and quantification of the microcirculation of the uterine cervix. The organized vascular patterns and optimal perfusion observed in healthy subjects allow for comparison with cervical pathology, for example in patients with cervical dysplasia or cervical cancer.

Abstract IA007: The mutational landscape of normal human endometrial epithelium

Abstract Human endometrium is a highly dynamic tissue that undergoes numerous cycles of breakdown, rapid repair and remodelling in response to the oscillating levels of oestrogen and progesterone. The marked regenerative capacity of the tissue’s epithelial compartment is maintained by the intra-glandular adult stem cells (ASCs) that are retained during menstruation. Although the endometrial epithelial ASCs were first described over a decade ago, they remain poorly characterised in comparison to their counterparts in other tissues, such as the small and arge intestine. In particular, the size of the stem cell pool within individual glands, clonal dynamics and genomic landscape are largely unknown. In this study, we laser-capture microdissected 257 morphologically normal endometrial glands from pre- and post-menopausal women (aged 19 to 81). In selected donors, we also obtained samples of normal endocervical and Fallopian tubular epithelium. Isolated cellular material was subjected to our modified library preparation protocol and subsequent whole genome sequencing (WGS). Analysis of the WGS data identified that the majority of the glands were clonal cell populations sharing a recent common ancestor. Somatic mutations accumulated at a rate of 29 substitutions per year. Total mutation burden in the normal endometrial epithelium is higher than in other normal cells and manyfold lower than in endometrial cancers. Overall, despite the heterogeneity in age, reproductive history and BMI, we found relatively homogenous mutational processes to be operative in this tissue with only occasional outliers. Remarkably, we not only identify recurrent acquisitions of certain cancer-associated mutations, particularly those that are advantageous to cell growth, proliferation and migration, but also show that such events occur early in life, potentially even before adolescence. Using a generalised linear mixed effect model, we found that age has a positive association with the accumulation of driver mutations, while parity has a negative association. Over time, the mutant ASCs serve as a reservoir for the acquisition of further driver mutations to the extent that in some cases, the entire sampled endometrium becomes ‘neoplastic’ on the genomic level while still retaining the apparently normal phenotype. Our data identify a distinct mutational landscape in normal endometrium that is in keeping with the presence of early positive selection in this highly regenerative tissue. Citation Format: Luiza Moore. The mutational landscape of normal human endometrial epithelium [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA007.

Müllerianosis de cuello uterino. Reporte de caso

La müllerianosis es una enfermedad embrionaria de los conductos de Müller o paramesonéfricos, que consiste en la mezcla de dos o más tipos de tejidos y que da como resultado la formación de adenomiosis, endometriosis, endosalpingiosis y endocervicosis. Con mayor frecuencia afecta la vejiga urinaria de las mujeres en edad fértil. La müllerianosis del cuello uterino es una afección benigna muy rara, con pocos casos reportados. La patogenia exacta sigue siendo tema de debate. Existen varias teorías sobre su etiología; las dos principales son la teoría de implantación y la metaplásica. Los síntomas varían desde su ausencia hasta dolor pélvico y dismenorrea. Generalmente aparece como tumor quístico con glándulas de diferentes tamaños revestidas por epitelio endometrial, endocervical o tubárico. Esta lesión podría confundirse con otras lesiones benignas, premalignas o malignas y es necesario la confirmación histopatológica. Debido a que es una enfermedad benigna, no necesita tratamiento adicional luego de la resección quirúrgica. Se presenta un caso de müllerianosis del cuello uterino.

The development of the human uterus: morphogenesis to menarche.

There is emerging evidence that early uterine development in humans is an important determinant of conditions such as ontogenetic progesterone resistance, menstrual preconditioning, defective deep placentation and pre-eclampsia in young adolescents. A key observation is the relative infrequency of neonatal uterine bleeding and hormone withdrawal at birth. The origin of the uterus from the fusion of the two paramesonephric, or Müllerian, ducts was described almost 200 years ago. The uterus forms around the 10th week of foetal life. The uterine corpus and the cervix react differently to the circulating steroid hormones during pregnancy. Adult uterine proportions are not attained until after puberty. It is unclear if the endometrial microbiome and immune response-which are areas of growing interest in the adult-play a role in the early stages of uterine development. The aim is to review the phases of uterine development up until the onset of puberty in order to trace the origin of abnormal development and to assess current knowledge for features that may be linked to conditions encountered later in life. The narrative review incorporates literature searches of Medline, PubMed and Scopus using the broad terms individually and then in combination: uterus, development, anatomy, microscopy, embryology, foetus, (pre)-puberty, menarche, microbiome and immune cells. Identified articles were assessed manually for relevance, any linked articles and historical textbooks. We included some animal studies of molecular mechanisms. There are competing theories about the contributions of the Müllerian and Wolffian ducts to the developing uterus. Endometrium features are suggestive of an oestrogen effect at 16-20 weeks gestation. The discrepancy in the reported expression of oestrogen receptor is likely to be related to the higher sensitivity of more recent techniques. Primitive endometrial glands appear around 20 weeks. Features of progestogen action are expressed late in the third trimester. Interestingly, progesterone receptor expression is higher at mid-gestation than at birth when features of endometrial maturation are rare. Neonatal uterine bleeding occurs in around 5% of neonates. Myometrial differentiation progresses from the mesenchyme surrounding the endometrium at the level of the cervix. During infancy, the uterus and endometrium remain inactive. The beginning of uterine growth precedes the onset of puberty and continues for several years after menarche. Uterine anomalies may result from fusion defects or atresia of one or both Müllerian ducts. Organogenetic differentiation of Müllerian epithelium to form the endometrial and endocervical epithelium may be independent of circulating steroids. A number of genes have been identified that are involved in endometrial and myometrial differentiation although gene mutations have not been demonstrated to be common in cases of uterine malformation. The role, if any, of the microbiome in relation to uterine development remains speculative. Modern molecular techniques applied to rodent models have enhanced our understanding of uterine molecular mechanisms and their interactions. However, little is known about functional correlates or features with relevance to adult onset of uterine disease in humans. Prepubertal growth and development lends itself to non-invasive diagnostics such as ultrasound and MRI. Increased awareness of the occurrence of neonatal uterine bleeding and of the potential impact on adult onset disease may stimulate renewed research in this area.

Matrix Metalloproteinases Expressed in Response to Bacterial Vaginosis Disrupt the Endocervical Epithelium, Increasing Transmigration of HIV.

Bacterial vaginosis (BV), a disorder of the female reproductive tract (FRT) in which a healthy Lactobacillus-dominant microflora is replaced by BV-associated bacteria (BVAB), can significantly increase the incidence of human immunodeficiency virus (HIV) acquisition. Discerning the effect of BV on the mucosal epithelium of the FRT may yield novel preventatives and therapeutics for HIV infection. Here, we investigated barrier dysfunction of the endocervix by host-derived factors, secreted in response to BV, as a potential cause of HIV infection. Using a polarized endocervical cell culture system, we determined that conditioned media (CM) from endocervical cells cocultured with BVAB (endocervical+BVAB CM), as well as cervicovaginal fluid (CVF) from women with BV, disrupted epithelial polarization. We assessed host matrix metalloproteinases (MMPs) as the BV-associated secreted factors which disrupt the endocervical epithelium. MMPs were overexpressed in endocervical+BVAB CM and CVF from women with BV and were capable of disrupting endocervical epithelial polarization. When we cocultured polarized endocervical cells with HIV-1-infected lymphocyte-derived cells, we discovered endocervical+BVAB CM and MMPs significantly increased the transmigration of virus through the epithelium, and treatment with an MMP inhibitor decreased these effects. When we examined the effect of CVF on HIV-1 transmigration through endocervical epithelium, we demonstrated that CVF samples with greater concentrations of BV-associated MMPs increased viral transmigration. Our results suggest MMPs increase HIV-1 infection by disrupting the endocervical epithelium, permitting transmigration of virus through the epithelium to infect underlying target cells.

Neisseria gonorrhoeae infects the heterogeneous epithelia of the human cervix using distinct mechanisms.

Sexually transmitted infections are a critical public health issue. However, the mechanisms underlying sexually transmitted infections in women and the link between the infection mechanism and the wide range of clinical outcomes remain elusive due to a lack of research models mimicking human infection in vivo. We established a human cervical tissue explant model to mimic local Neisseria gonorrhoeae (GC) infections. We found that GC preferentially colonize the ectocervix by activating integrin-β1, which inhibits epithelial shedding. GC selectively penetrate into the squamocolumnar junction (TZ) and endocervical epithelia by inducing β-catenin phosphorylation, which leads to E-cadherin junction disassembly. Epithelial cells in various cervical regions differentially express carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), the host receptor for GC opacity-associated proteins (OpaCEA). Relatively high levels were detected on the luminal membrane of ecto/endocervical epithelial cells but very low levels intracellularly in TZ epithelial cells. CEACAM-OpaCEA interaction increased ecto/endocervical colonization and reduced endocervical penetration by increasing integrin-β1 activation and inhibiting β-catenin phosphorylation respectively, through CEACAM downstream signaling. Thus, the intrinsic properties of cervical epithelial cells and phase-variation of bacterial surface molecules both play a role in controlling GC infection mechanisms and infectivity, preferential colonization or penetration, potentially leading to asymptomatic or symptomatic infection.