Systematic review and meta-analysis of the effects of treatment and immunization against schistosomiasis

Schistosomiasis is a water-borne parasitic disease of great public health importance mainly in sub-Saharan African countries. The majority of current control programmes use the antihelminthic drug praziquantel to reduce disease burden in endemic areas. Praziquantel treatment has been reported to accelerate the development of protective immunity against re-infection that otherwise takes years to develop. To date, there is no licensed vaccine for schistosomiasis in humans but an attenuated schistosome parasite vaccine has been tested in animal models. Employing systematic review and meta-analysis approaches, my PhD research has four main objectives relating to attenuated schistosome vaccine and praziquantel treatment: 1) to identify predictors that determine protection levels after treatment with attenuated Schistosoma mansoni vaccines in the mouse model, 2) to quantify the influence of host and schistosome parasite species on attenuated parasite vaccine efficacy, 3) to explore the direction of change (increase/decrease) in schistosome parasite-specific antibody isotypes after praziquantel treatment in humans, 4) to identify predictors of praziquantel efficacy in humans. My analyses revealed three factors that have an influence on the protection levels provided by attenuated schistosome parasite vaccines: increasing numbers of immunizing parasites had a positive effect on the levels of protection whereas increasing the radiation dose and the time to challenge infection had negative effects. Analyses showed that the attenuated schistosome vaccine has the potential to achieve protection levels as high as 79% after a single dose in mice. Alongside this, baboon studies consistently reported protective effects of attenuated schistosome vaccines against re-infection. These results show there is a high potential for an attenuated schistosome parasite vaccine to be effective in humans. A meta-analysis of the influence of praziquantel treatment on the direction of change in schistosome-specific antibody isotypes was conducted. The analysis revealed considerable variability in the antibodies’ direction of change among populations. The results also demonstrated an increase of anti-worm IgA and IgE in the majority of studies. These antibodies have been reported to have a protective effect against re-infection. The combination of age and infection intensity, and the number of days after treatment were identified as influential predictors for some antibody isotypes, but there was no single predictor that consistently affected all antibody isotypes in the same way. Praziquantel efficacy levels in humans were investigated and the analyses revealed that cure rates for schistosomiasis increase with praziquantel dose, and were affected by the identity of the schistosome parasite species (S. mansoni vs. S. haematobium) and the age of the participants (children: 0-19 years old vs. adults: ≥ 20 years old). There has been no clear efficacy level reduction over the treatment years (1979-2013) suggesting that praziquantel is still effective in the treatment of schistosomiasis despite concerns about possible resistance. The development of a schistosome vaccine will benefit from a closer investigation into the mechanisms through which protection is acquired in attenuated schistosome parasite vaccine studies showing high potential efficacy in animal models. Nevertheless, it will take time to develop a schistosome vaccine for human use. The uptake of the vaccine will be made even more challenging by the lack of adequate infrastructure in schistosomiasis endemic areas. In the meantime, close monitoring of praziquantel efficacy levels is necessary to confirm the effectiveness of schistosomiasis control in endemic areas

Efficacy of praziquantel has been maintained over four decades (from 1977 to 2018):A systematic review and meta-analysis of factors influence its efficacy

BackgroundThe antihelminthic drug praziquantel has been used as the drug of choice for treating schistosome infection for more than 40 years. Although some epidemiological studies have reported low praziquantel efficacy in cure rate (CR) and/or egg reduction rate (ERR), there is no consistent robust evidence of the development of schistosome resistance to praziquantel (PZQ). There is need to determine factors that lead to variable treatment CR and/or ERR. Therefore, we conducted a systematic review and meta-analysis to review CR and ERR as well as identify their predictors.Methodology/principal findingsIn this systematic review and meta-analysis, a literature review was conducted using Biosis Citation Index, Data Citation Index, MEDLINE, and Web of Science Core Collection all of which were provided through Web of Science. Alongside these, EMBASE, and CAB abstracts were searched to identify relevant articles. Random effect meta-regression models were used to identify the factors that influence CR and/or ERR by considering differences in host characteristics and drug dose. In total, 12,127 potential articles were screened and 146 eligible articles (published from 1979 to 2020) were identified and included for the meta-analysis. We found that there has been no significant reduction in CR or ERR over the study period. The results showed more variability in CR, compared with ERR which was more consistent and remained high. The results showed a positive effect of "PZQ treatment dose" with the current recommended dose of 40 mg/kg body weight achieving 57% to 88% CR depending on schistosome species, age of participants, and number of parasitological samples used for diagnosis, and ERR of 95%.Conclusions/significanceBased on a review of over 40 years of research there is no evidence to support concerns about schistosomes developing resistance to PZQ. These results indicate that PZQ remains effective in treating schistosomiasis

Application of RFLP-PCR-Based Identification for Sand Fly Surveillance in an Area Endemic for Kala-Azar in Mymensingh, Bangladesh

Mymensingh is the most endemic district for kala-azar in Bangladesh. Phlebotomus argentipes remains the only known vector although a number of sand fly species are prevalent in this area. Genotyping of sand flies distributed in a VL endemic area was developed by a PCR and restriction-fragment-length polymorphism (RFLP) of 18S rRNA gene of sand fly species. Using the RFLP-PCR analysis with AfaI and HinfI restriction enzymes, P. argentipes, P. papatasi, and Sergentomyia species could be identified. Among 1,055 female sand flies successfully analyzed for the species identification individually, 64.4% flies was classified as Sergentomyia species, whereas 35.6% was identified as P. argentipes and no P. papatasi was found. Although infection of Leishmania within the sand flies was individually examined targeting leishmanial minicircle DNA, none of the 1,055 sand flies examined were positive for Leishmania infection. The RFLP-PCR could be useful tools for taxonomic identification and Leishmania infection monitoring in endemic areas of Bangladesh

Extracellular vesicles derived from SARS-CoV-2 M-protein-induced triple negative breast cancer cells promoted the ability of tissue stem cells supporting cancer progression

IntroductionSARS-CoV-2 infection increases the risk of worse outcomes in cancer patients, including those with breast cancer. Our previous study reported that the SARS-CoV-2 membrane protein (M-protein) promotes the malignant transformation of triple-negative breast cancer cells (triple-negative BCC).MethodsIn the present study, the effects of M-protein on the ability of extracellular vesicles (EV) derived from triple-negative BCC to regulate the functions of tissue stem cells facilitating the tumor microenvironment were examined.ResultsOur results showed that EV derived from M-protein-induced triple-negative BCC (MpEV) significantly induced the paracrine effects of adipose tissue-derived mesenchymal stem cells (ATMSC) on non-aggressive BCC, promoting the migration, stemness phenotypes, and in vivo metastasis of BCC, which is related to PGE2/IL1 signaling pathways, in comparison to EV derived from normal triple-negative BCC (nEV). In addition to ATMSC, the effects of MpEV on endothelial progenitor cells (EPC), another type of tissue stem cells, were examined. Our data suggested that EPC uptaking MpEV acquired a tumor endothelial cell-like phenotype, with increasing angiogenesis and the ability to support the aggressiveness and metastasis of non-aggressive BCC.DiscussionTaken together, our findings suggest the role of SARS-CoV-2 M-protein in altering the cellular communication between cancer cells and other non-cancer cells inside the tumor microenvironment via EV. Specifically, M-proteins induced the ability of EV derived from triple-negative BCC to promote the functions of non-cancer cells, such as tissue stem cells, in tumorigenesis