Archives of Microbiology

Role of human papillomavirus (HPV) variants and host genetic susceptibility in cervical carcinogenesis

Cervical carcinoma continues to be one of the leading causes of cancer-related mortality among women worldwide, disproportionately striking developing regions, including India. High-risk persistent HPV infection has long been recognized as the central etiological factor in cervical carcinogenesis; however, not all infected women end up with malignancy, indicating the role of viral genomic variation and host genetic susceptibility. High-risk HPV variants, primarily comprising lineage clusters of HPV16 and HPV18, exhibit differential oncogenic potential due to mutations in the E6/E7 oncogenes and the LCR, which is responsible for viral persistence, the efficiency of p53/pRb degradation, immune evasion, and epithelial cell transformation. Genetic polymorphisms in the host regulate the natural history of infection and cervical cancer risk. Variants of HLA class I/II alleles influence antigen presentation and Single nucleotide polymorphism in immune regulatory cytokine genes (IL-10, TNF-α, IFN-γ), TP53 codon 72 (Arg/Pro), DNA repair and metabolic genes (XRCC1, MTHFR), and detoxification gene null genotypes (GSTM1, GSTT1) modulate viral persistence, oxidative DNA damage response, and oncogenic progression. Advancements such as next-generation sequencing and immunogenetics, which identify the relationship between HPV variants and host immune genes that modulate disease susceptibility, vaccine responsiveness, and progression patterns across various genetic backgrounds. This review systematically integrates molecular mechanisms of HPV variant-induced oncogenesis and host genetic susceptibility with emphasis on population-based variability in addition to evidence culled from meta-analyses and GWAS data for immune regulation, DNA repair, as well as host single nucleotide polymorphisms in different populations and its implications for personalized prevention measures, screening, and vaccine response.

Detection of high-risk human papillomavirus infected cervical biopsies samples by immunohistochemical expression of the p16 tumor marker

Cervical cancer is the fourth most common type of cancer in women worldwide. It is widely accepted that the main cause of cervical cancer, especially in underdeveloped countries like Pakistan, is the infection caused by the human papillomavirus (HPV). The current screening and diagnostic methods face several challenges in accurately detecting the various types of lesions caused by HPV. Therefore, the present study was conducted to assess the effectiveness of p16 immunohistochemistry (IHC) analysis as a diagnostic method in samples of cervical biopsies. One hundred cervical biopsy samples were obtained from female patients across various age groups (> 20- ≤ 30, > 31- ≤ 40, > 41- ≤ 50, > 51- ≤ 60 years). These samples were subsequently prepared for subsequent examination. All samples were analyzed using automated tissue processing followed by Hematoxylin and Eosin (H & E) staining, and p16 IHC tumour marker staining. The H & E slides showed changes in normal cervical tissues, while four cervical abnormalities were identified statistically significant using p16 marker including chronic cervicitis, nabothian cyst formation, cervical intraepithelial neoplasia, and cervical cancers (P value 0.014). Furthermore, among females of different age groups (> 31- ≤ 40, > 41- ≤ 50, > 51- ≤ 60 years) were found statistically significant suffering from cervical cancer (P value 0.04), HPV with cervical cancer (P value 0.01), HPV with cervical intraepithelial neoplasia (P value 0.01). Based on the available data, it can be inferred that the incorporation of the p16 tumor marker may be a valuable method for detecting high-risk HPV in cervical biopsies samples.

Cervicovaginal microbiota isolated from healthy women exhibit probiotic properties and antimicrobial activity against pathogens isolated from cervical cancer patients

Abnormal cervicovaginal microbiota play an important role in HPV persistence and progression to cervical cancer. The present study aimed at isolating and identifying potential probiotics from vaginal swabs of healthy women and evaluating their activity against vaginal pathogens isolated from cervical cancer patients. Based on probiotic, acid-bile tolerance and antimicrobial properties, 13 lactic acid bacteria (LAB) from the healthy group were identified by MALDI TOF MS (Matrix Assisted Laser Desorption and Ionisation, Time Of Flight Mass Spectrometry). Among these, four strains, Lactobacillus gasseri P36Mops, Limosilactobacillus fermentum P37Mws, Lactobacillus delbrueckii P31Mcs and Enterococcus faecium P26Mcm, exhibited significant antimicrobial activity against 8 vaginal pathogens (Staphylococcus haemolyticus P41Tcs, Escherichia coli P30Tcs, E. coli P79Bcm, Enterococus faecalis P29Mops, E. faecalis P50Tws, E. faecalis P68Tcb, S. haemolyticus P48Bcb and S. haemolyticus P58Bcb) isolated from precancerous and cervical cancer patients. 16S rRNA sequencing of four potential probiotics revealed congruency with the MALDI-TOF MS identification and phylogenetic analysis showed genetic relationship with previously reported LAB strains. The selected LAB showed strain specific hydrophobicity (35.88-56.70%), auto-aggregation (35.26-61.39%) and antibiotic susceptibility. Interestingly, L. gasseri P36Mops was resistant to five standard antibiotics routinely used against urogenital or vaginal infections. LCMS (Liquid Chromatography Mass Spectrometry) analyses of the CFS (cell-free supernatant) of the four potential probiotics revealed the presence of metabolites such as N-(1-deoxy-1-fructosyl)valine, hygroline, acetoxy-2-hydroxy-16-heptadecen-4-one, avocadyne 4-acetate, avocadyne 2-acetate, taraxinic acid glucosyl ester, 6-hydroxypentadecanedioic acid, with reported antimicrobial activity. The overall data suggest the bio-therapeutic potential of the identified vaginal probiotics against cervical cancer-associated pathogens.

Cervical cancer and vaginal microbiota changes

Microbial changes in vaginal ecosystem may accelerate the process of cervical carcinogenesis. The developed cervical cancer can lead to changes in the vaginal microbiota. The aim of our study is to determine the vaginal microbiota changes at women with FIGO I stage cervical cancer. We conducted an open, single-site survey in the Department of Gynecology of the Military Medical Academy in Sofia, Bulgaria, from 2014 to 2019 year. The study included a total of 32 women aged 38-55 years with clinical and pathology established cervical cancer (FIGO I stage). The underlying vaginal DNA microbiological test indicated presence or absence of bacterial vaginosis, other vaginal infections or normal vaginal microbiota. Of 32 (100%) women enrolled in our study, 19 (59.4%) was with FIGO IA stage cervical cancer and 13 (40.6%) with IB stage. Disturbances of vaginal microbiota in we found at 23 (71.9%) of women with cervical cancer included in our study. At the rest of 9 (28.1%) women we found out normal vaginal microbiota. Bacterial vaginosis was determined clinically and microbiologically in 15 (46.9%) women enrolled in the study. Aerobic vaginitis caused by Streptococcus species we establish at 4 (12.5%) of women. Trichomonas vaginalis infection have 1 (3.1%) women and Candida Albicans the last one 1 (3.1%) from this group with disturbed vaginal microbial balance. Bacterial dysbacteriosis, characterized by a predominance of Gardnerella vaginalis alone or in complex with other anaerobic bacteria, aerobic vaginitis and other sexually transmitted vaginal pathogens from one side and a concomitant paucity of vaginal Lactobacillus species may be an HPV-dependent cofactor for cervical neoplasia development. Only with this single observation it is difficult to confirm that vaginal microbiota dysbiosis contributes to HPV infection and carcinogenesis.