Journal of Infection

Gram-negative intratumoral bacteria mediate lymph node metastasis through LPS-TLR4/MAPK signaling pathway in cervical cancer

Intratumoral bacteria have been identified as prevalent in various solid tumors, playing a significant role in tumor progression. Lymph node metastasis is a major clinical feature and the primary cause of mortality in cervical cancer (CC). However, the effect of intratumoral bacteria on lymphatic node metastasis in CC remains unclear. This study employed 16S rDNA sequencing and targeted bacterial culture to investigate the distribution of intratumoral bacteria in human CC tissues. The identified Gram-negative bacteria, including Escherichia coli (E. coli), Prevotella bivia (P. bivia), and Fusobacterium nucleatum (F. nucleatum), were isolated, and their roles in metastasis were examined using in vitro transwell and capillary tube formation assays on human lymphatic endothelial cells (HLEC). The signaling pathways involved in metastasis were assessed by examining TLR4/MAPK activation and the expression of prometastatic factors EFNA1 and EDN2. In vivo studies using a mouse footpad tumorigenesis model were also conducted to observe the effect of LPS, which was extracted from these three gram-negative intratumoral bacteria and E. coli on lymph node metastasis. A higher abundance of Gram-negative bacteria, especially in metastatic CC tissues, was observed. E. coli, P. bivia, and F. nucleatum enhanced capillary tube formation in lymphatic endothelial cells and facilitated metastasis of uninfected tumor cells through paracrine signaling. These bacteria activated the TLR4/MAPK signaling pathway via lipopolysaccharide (LPS), leading to the upregulation of prometastatic factors EFNA1 and EDN2. Knockdown of EFNA1 and EDN2 attenuated the bacteria-induced metastasis, whereas overexpression of these factors mimicked the effects of bacterial infection. In vivo, LPS, which was extracted from E. coli, P. bivia, and F. nucleatum and live E. coli promoted lymph node metastasis, with elevated LPS levels and MAPK-EFNA1/EDN2 expression observed in infected mice compared to controls. The study suggests that Gram-negative bacteria, particularly E. coli, P. bivia, and F. nucleatum, play a causal role in exacerbating lymph node metastasis in CC. These findings highlight the potential of targeting these bacteria and their associated signaling pathways as therapeutic strategies to improve clinical outcomes in CC patients.

Prevalence of cervicovaginal human papillomavirus infection and genotypes in the pre-vaccine era in China: A nationwide population-based study

The HPV vaccine has been licensed in mainland China since 2017. This study aimed to assess the epidemiological characteristics of HPV genotypes in the pre-vaccine era in China. We conducted a multicentric population-based study nested in the largest health clinic chain in China. Between January 1, 2017 and December 31, 2017, 427,401women aged 20 years or older with polymerase chain reaction-based HPV genotyping tests were included in the study. The cervicovaginal infection of 14 high-risk HPV genotypes and 9 low-risk genotypes was assessed using adjusted prevalence, multivariable logistic regression, cluster analysis, and heatmap. HPV prevalence was 15.0% (95% confidence interval [CI]: 14.1-15.9%) in China, with high- and low-risk genotypes being 12.1% (95%CI: 11.4-12.7%) and 5.2% (95%CI: 4.8-5.7%), respectively. The prevalence of HPV genotypes corresponding to bivalent, quadrivalent, and nonavalent vaccines were 2.1%, 2.4%, and 8.3%, respectively, whereas the prevalence of non-vaccine high-risk genotypes was 5.7%. The most common high-risk genotypes were HPV-52 (3.5%), HPV-58 (2.1%), and HPV-16 (1.6%), and the prevalence of HPV-18 (0.6%), HPV-6 (0.1%), and HPV-11 (0.2%) were relatively low. Infection with HPV genotypes differed significantly across age groups and geographic locations. HPV prevalence was high in the pre-vaccine era in China, and a population-based HPV vaccination strategy is needed in the future.

Age-specific prevalence of high-risk human papillomavirus infection among women in rural China, 2016–2018

Characteristics of genotypes and prevalence of high-risk human papillomavirus in different economic development regions in China

Novel evidence revealed genetic association between COVID-19 infection, severity and endometrial cancer

Ureaplasma parvum serovar 6 may be a novel element in the progression of HPV infection to CIN: A cross-sectional study of 7058 women

Ureaplasma parvum (U. parvum) is generally regarded as innocuous, and studies focusing on variations in pathogenicity among U. parvum serovars are inadequate. We elucidated the variations in the pathogenicity of U. parvum serovars in promoting human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN). This cross-sectional study used baseline data from a Chinese multicenter prospective cohort of women of childbearing age undergoing routine cervical cancer screening. We employed multivariate logistic regression analysis to estimate the pathogenic effects of specific U. parvum serovars on HPV infection and CIN. Causal mediation analysis was performed to ascertain the direct effects of specific U. parvum serovars on CIN and their indirect implications via HPV infection. The final data analysis encompassed 7058 participants. Upon adjusting for confounding factors, a positive association was observed between U. parvum serovars 1, 3, and 6 and HPV infection (OR 1.53, 95%CI 1.15-2.03; OR 1.31, 95%CI 1.06-1.64; OR 2.34, 95%CI 1.90-2.87); however, only participants with U. parvum serovar 6 showed an increased risk of CIN (OR 1.90, 95%CI 1.19-3.02). No substantial correlation was observed between U. parvum serovar 14 and HPV or CIN incidence. HPV infection potentially mediates the influence of U. parvum serovar 6 on CIN, with a mediation proportion of 76.66%. Our findings suggest that different U. parvum serovars vary in pathogenicity regarding HPV and CIN. Early detection of specific U. parvum serovars, such as U. parvum serovar 6, in HPV-infected individuals may enable early intervention therapies and reduce the risk of CIN development.

Prevalence and genotype distribution of high-risk human papillomavirus infection among Chinese women aged 35–64: A national screening population-based study

To investigate the prevalence, genotype distribution, and associations of HR-HPV infection with cervical lesion grades among Chinese women aged 35-64 years. A cross-sectional analysis was conducted using data from women aged 35-64 years who participated in China's national cervical cancer screening program across 13 provinces in 2021. HR-HPV testing was performed at local laboratories using clinically validated assays approved in China, including pooled detection and genotype-specific platforms following standardized national protocols. Epidemiological characteristics were analyzed in 445,045 women, and genotype distribution was assessed in 113,149 women with available genotyping results. Group differences were assessed using chi-square tests, and factors associated with HR-HPV infection were further explored using multivariable logistic regression. The overall prevalence of HR-HPV infection was 10.42% (95% CI: 10.33-10.51). Significant regional variation was observed, with higher prevalence in Western China (11.48%; 95% CI: 11.30-11.66) and Central China (11.46%; 95% CI: 10.98-11.96), and lower prevalence in Northeastern China (9.12%; 95% CI: 8.89-9.36). HR-HPV prevalence increased with age, peaking in women aged 60-64 years (12.69%; 95% CI: 12.30-13.09). The most prevalent genotypes were HPV52 (2.36%), HPV16 (1.73%), and HPV58 (1.40%). Single infections predominated among HR-HPV positive women (87.91%). HPV16 was the most frequently detected genotype across all cervical lesion grades, while HPV52 (10.35%) and HPV58 (9.69%) accounted for a higher proportion of high-grade lesions than HPV18 (7.27%). HR-HPV infection remains prevalent among Chinese women, and these population-level findings may help inform age- and region-specific cervical cancer screening strategies and provide epidemiological evidence relevant to HPV vaccination planning.

Urinary HPV DNA testing as a tool for cervical cancer screening in women who are reluctant to have a Pap smear in France

In France, cervical cancer screening is based on human papillomavirus (HPV) testing on cervical samples (women aged 30-65) and cytological examination of Pap smears (25-29), but screening coverage is unsatisfactory. The CapU3 study aimed to propose urinary HPV testing on 13,535 women aged 35 to 65 who had not had a Pap smear since 2010. High-risk HPV (HR-HPV) detection was performed using a real-time PCR (Anyplex II HPV 28 Detection, Seegene®). Women with HR-HPV positive results were encouraged to have a cervical smear as soon as possible to detect the presence of cervical lesions. The participation rate was 15.4%. Out of the 1,915 analyzed specimens, 1,711 and 190 were negative and positive, respectively, for at least 1 HR-HPV genotype. HR-HPV genotypes other than HPV-16 or HPV-18 were mostly detected as HPV-53 (23.7%) and HPV-68 (14.2%). A satisfactory gynecological follow-up was observed for HPV-positive women (92.1%). 23 abnormal smears were observed and eight high-grade cytological lesions after colposcopy and biopsy were diagnosed. As home HPV urinary testing is non-invasive and does not require medical attention, this method may be an alternative for women who are reluctant to have a Pap smear and thus extend screening coverage.