| 1. |
- Mukanyangezi, Marie Francoise
(author)
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Natural History of Human Papillomavirus Infections and Other Sexually Transmitted Infections in Rwanda-Immunological Aspects of the Uterine Cervix
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Objective: Cervical cancer stands for the predominant cause of cancer death among Rwandan women. Chronic Human Papillomavirus (HPV) infection constitutes the main risk factor. We here assessed the prevalence and incidence of high-risk (HR)- and low-risk (LR)-HPVs, low-grade and high-grade squamous intraepithelial lesions (LSIL and HSIL) and cancer and associated risk factors in 400 HIV- and HIV+ Rwandan women. Whether HPV testing could serve as a screening method for detecting HSIL was analyzed. We also assessed the prevalence and curing rates of different sexually transmitted infections (STIs) and sexual behaviour. Advanced cervical cancer is often treated with radiotherapy. In an animal model for radiation cervicitis, we wanted to assess how the normal uterine cervix responds to ionization radiation and whether hyperbaric oxygen therapy (HBOT) may reverse these responses. Methods: Women were interviewed, screened for STIs (baseline and 9 months) and underwent cervical sampling for cytology and a test for 37 HPV strains. Cytological samples were taken again 9, 18 and 24 months later in 100 HIV- and 137 HIV+ women. We explored whether the single nucleotide polymorphism (SNP) rs1297860 in IL28B correlates with susceptibility to HPV infection and persistence as well as the development of SILs. In the preclinical studies, rats underwent cervical irradiation and were either exposed to HBOT or no intervention. Immunological and oxidative responses induced by radiation were assessed and whether HBOT was able to reverse these responses. Results: HPV16 and HPV52 were the most common HPV strains. The sensitivity was 78% and the specificity 87% to detect HSIL with HPV screening. Chronic and incident HR-HPV infections occurred more frequently in HIV+ women than in HIV- women. HSIL or cancer was diagnosed in 38% of HIV+ women with persistent HR-HPV infections. The C/T and T/T genotypes of the IL28B SNP rs12979860 were more common in the group of women contracting HPV compared with women not contracting HPV. STIs were common in Rwandan women and the use of condoms was not affected by present STIs. TLR5, TRIF, NF-κB, oxidative stress (8-OHdG) and antioxidant enzymes (SOD-1 and catalase) were up regulated, while cytokines were down-regulated 14 days after cervical irradiation. Changes in 8-OHdG and catalase were normalized after HBOT. Conclusions: HPVs and STIs are common among Rwandan women. HPV screening may be of particular importance if provided for risk patients such as HIV+ women that develop more often persistent HPV infections and HSIL. Ionizing radiation induces oxidative stress and immune responses in the cervix that may be reversed by HBOT.
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| 2. |
- Mukanyangezi, Marie Francoise, et al.
(author)
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Persistence rate of cervical human papillomavirus infections and abnormal cytology in Rwanda
- 2019
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In: HIV Medicine. - : Wiley. - 1464-2662 .- 1468-1293. ; 20:7, s. 485-495
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Journal article (peer-reviewed)abstract
- Objectives In this study, we determined the incidence and persistence of human papillomavirus (HPV) strains and of squamous intraepithelial lesions (SIL) or worse cytology in 237 HIV-positive and HIV-negative Rwandan women and whether the interleukin (IL)-28B single nucleotide polymorphism (SNP) at rs12979860 correlated with susceptibility to and persistence of HPV infection. Methods Cervical samples were collected at baseline and after 9, 18 and 24 months for a 40-HPV DNA screening test and a ThinPrep Pap test. Genotyping of the IL-28B SNP rs12979860 was performed using real-time polymerase chain reaction (PCR). Results Chronic high-risk (HR) HPV infections occurred in 56% of HIV-positive women, while no HIV-negative women developed HPV chronicity. High-grade SIL (HSIL) or cancer was diagnosed in 38% of HIV-positive women with persistent HR-HPV infections. HIV and HR-HPV positivity at baseline were factors associated with an increased risk of HPV persistence. Additionally, HR-HPV positivity at baseline was associated with an increased risk of developing HSIL or worse cytology. The unfavourable T/x genotype at rs12979860 is common among Africans, and women with this genotype were found to be more commonly infected with HPV. Conclusions HPV screening in Rwanda may help to identify women at risk of developing cervical cancer and polymorphism in IL-28B may be associated with risk of contracting HPV infection.
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| 3. |
- Mukanyangezi, Marie Francoise, et al.
(author)
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Radiation induces changes in toll-like receptors of the uterine cervix of the rat
- 2019
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:4
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Journal article (peer-reviewed)abstract
- Radiotherapy is an important therapeutic approach against cervical cancer but associated with adverse effects including vaginal fibrosis and dyspareunia. We here assessed the immunological and oxidative responses to cervical irradiation in an animal model for radiation-induced cervicitis. Rats were sedated and either exposed to 20 Gy of ionising radiation given by a linear accelerator or only sedated (controls) and euthanized 1-14 days later. The expressions of toll-like receptors (TLRs) and coupled intracellular pathways in the cervix were assessed with immunohistofluorescence and western blot. Expression of cytokines were analysed with the Bio-Plex Suspension Array System (Bio-Rad). We showed that TLRs 2-9 were expressed in the rat cervix and cervical irradiation induced up-regulation of TLR5, TRIF and NF-kappa B. In the irradiated cervical epithelium, TLR5 and TRIF were increased in concert with an up-regulation of oxidative stress (8-OHdG) and antioxidant enzymes (SOD-1 and catalase). G-CSF, M-CSF, IL-10, IL-17A, IL-18 and RANTES expressions in the cervix decreased two weeks after cervical irradiation. In conclusion, the rat uterine cervix expresses the TLRs 2-9. Cervical irradiation induces immunological changes and oxidative stress, which could have importance in the development of adverse effects to radiotherapy.
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| 4. |
- Mukanyangezi, Marie Francoise, et al.
(author)
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Screening for human papillomavirus, cervical cytological abnormalities and associated risk factors in HIV-positive and HIV-negative women in Rwanda.
- 2018
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In: HIV medicine. - : Wiley. - 1468-1293 .- 1464-2662. ; 19:2, s. 152-166
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Journal article (peer-reviewed)abstract
- Cervical cancer is the major cause of death from cancer in Africa. We wanted to assess the prevalence of human papillomavirus (HPV) infections and associated risk factors and to determine whether HPV testing could serve as a screening method for squamous intraepithelial lesions (SILs) in Rwanda. We also wanted to obtain a broader understanding of the underlying risk factors for the establishment of HPV infection in Rwanda.A total of 206 HIV-positive women, 172 HIV-negative women and 22 women with unknown HIV status were recruited at the University Teaching Hospitals of Kigali (UTHK) and of Butare (UTHB) in Rwanda. Participants underwent an interview, cervical sampling for a Thinprep Pap test and a screening test analysing 37 HPV strains.Only 27% of HIV-positive women and 7% of HIV-negative women had been screened for cervical cancer before. HPV16 and HPV52 were the most common HPV strains. HIV-positive women were more commonly infected with high-risk (HR) HPV and multitype HPV than HIV-negative women. The sensitivity was 78% and the specificity 87% to detect high-grade SIL (HSIL) with HPV screening. Among HIV-negative women, being divorced was positively associated with HR-HPV infection, while hepatitis B, Trichomonas vaginalis infection and HR-HPV infection were factors positively associated with SILs. Ever having had gonorrhoea was positively associated with HR-HPV infection among HIV-positive women. HR-HPV infection and the number of live births were positively associated with SILs.The currently used quadrivalent vaccine may be insufficient to give satisfactory HPV coverage in Rwanda. HPV Screening may be effective to identify women at risk of developing cervical cancer, particularly if provided to high-risk patients.
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| 5. |
- Mukanyangezi, Marie Francoise, et al.
(author)
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Sexual risk behaviour in a cohort of HIV-negative and HIV-positive Rwandan women
- 2019
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In: Epidemiology and Infection. - : Cambridge University Press (CUP). - 0950-2688 .- 1469-4409. ; 147
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Journal article (peer-reviewed)abstract
- Here we wanted to assess whether sexual risk behaviour differs dependent by human immunodeficiency virus (HIV) status by following 100 HIV- and 137 HIV+ women recruited at two university teaching hospitals in Rwanda. Women were tested for sexually transmitted infections (STIs; trichomoniasis, syphilis, hepatitis B and C) and for reproductive tract infections (RTIs; candidiasis, bacterial vaginosis (BV)) and were interviewed at baseline and 9 months later. BV was the most prevalent infection, while syphilis was the most common STI with a 9-month incidence of 10.9% in HIV+ women. Only 24.5% of women positive for any RTI/STI contacted their health facility and got treatment. More HIV- women than HIV+ women had had more than one sexual partner and never used condoms during the follow-up period. The use of condoms was affected neither by marital status nor by concomitant STIs besides HIV. Our data highlight the importance of public education regarding condom use to protect against STIs in an era when HIV no longer is a death sentence.
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| 6. |
- Podmolíková, Lucie, et al.
(author)
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Cholinergic regulation of proliferation of the urothelium in response to E. coli lipopolysaccharide exposition.
- 2018
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In: International immunopharmacology. - : Elsevier BV. - 1878-1705 .- 1567-5769. ; 56, s. 222-229
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Journal article (peer-reviewed)abstract
- How the proliferation of the urothelium is regulated is known to a little degree. E. coli lipopolysaccharide (LPS) activates the innate immune response of the urinary bladder via the Toll-like receptor 4 (TLR4) on the urothelium but induces also urothelial proliferation. We wanted to assess whether muscarinic receptors are involved in the regulation of urothelial proliferation triggered by LPS stimulation. Female Fischer 344 rats were instilled with LPS or saline (control) in the urinary bladder in the absence or presence of muscarinic receptor blockade with atropine and regeneration of the urothelium was assessed 4h and 24h later. In the Fischer 344 bladder, urothelial thinning and urothelial caspase 3 up-regulation occurred at 4h after LPS urinary bladder instillation, which were totally blocked in rats pre-treated with atropine. TLR4 was only expressed in blood vessels in the Fischer 344 bladder, while it was also expressed in umbrella cells in the Sprague-Dawley bladder. Proliferation (Ki67 incorporation) of the human urothelial cell line UROtsa was reduced in the presence of the muscarinic receptor antagonists methoctramine (M2/M4-selective) and pirenzepine (M1/M4-selective), while proliferation instead was enhanced in the presence of atropine. In UROtsa cells exposed to LPS for 24h, 4-DAMP (M3/M1/M5-selective) inhibited instead proliferation. In conclusion, muscarinic receptors regulate urothelial proliferation and LPS may induce urothelial apoptosis via muscarinic receptor-dependent pathways. Our findings also suggest that species differences exist in the expressional pattern of TLR4 in the urothelium.
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| 7. |
- Podmolíková, Lucie, et al.
(author)
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Radiation of the urinary bladder attenuates the development of lipopolysaccharide-induced cystitis
- 2020
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In: International Immunopharmacology. - : Elsevier BV. - 1567-5769 .- 1878-1705. ; 83
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Journal article (peer-reviewed)abstract
- © 2020 Elsevier B.V. In the present study we assessed how ionizing radiation affects TLR4-stimulated immune activation in lipopolysaccharide (LPS)-induced cystitis. LPS or saline was administered intravesically to female rats followed by urinary bladder irradiation (20 Gy) 24 h later or sham treatment. Presence in the urinary bladder of inflammatory cells (mast cells, CD3+, ionized calcium-binding adapter molecule 1 (Iba-1)+, CD68+, CD40+, CD80+, CD11c + and CD206 + cells) and expression of oxidative stress (8-OHdG), hypoxia (HIF1α) and anti-oxidative responses (NRF2, HO-1, SOD1, SOD2, catalase) were assessed 14 days later with western blot, qPCR and/or immunohistochemistry. LPS stimulation resulted in a decrease of Iba-1 + cells in the urothelium, an increase in mast cells in the submucosa and a decrease in the bladder protein expression of HO-1, while no changes in the bladder expression of 8-OHdG, NRF2, SOD1, SOD2, catalase and HIF1α were observed. Bladder irradiation inhibited the LPS-driven increase in mast cells and the decrease in Iba1 + cells. Combining LPS and radiation increased the expression of 8-OHdG and number of CD3-positive cells in the urothelium and led to a decrease in NRF2α gene expression in the urinary bladder. In conclusion, irradiation may attenuate LPS-induced immune responses in the urinary bladder but potentiates LPS-induced oxidative stress, which as a consequence may have an impact on the urinary bladder immune sensing of pathogens and danger signals.
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