Pub Date : 2023-10-04DOI: 10.3389/fpara.2023.1242727
Deninson Alejandro Vargas, David J. Gregory, Roni Nitzan Koren, Dan Zilberstein, Ashton Trey Belew, Najib M. El-Sayed, María Adelaida Gómez
Host cell functions that participate in the pharmacokinetics and pharmacodynamics (PK/PD) of drugs against intracellular pathogen infections are critical for drug efficacy. In this study, we investigated whether macrophage mechanisms of xenobiotic detoxification contribute to the elimination of intracellular Leishmania upon exposure to pentavalent antimonials (Sb V ). Primary macrophages from patients with cutaneous leishmaniasis (CL) (n=6) were exposed ex vivo to L. V. panamensis infection and Sb V , and transcriptomes were generated. Seven metallothionein (MT) genes, potent scavengers of heavy metals and central elements of the mammalian cell machinery for xenobiotic detoxification, were within the top 20 up-regulated genes. To functionally validate the participation of MTs in drug-mediated killing of intracellular Leishmania , tandem knockdown (KD) of MT2-A and MT1-E, MT1-F, and MT1-X was performed using a pan-MT shRNA approach in THP-1 cells. Parasite survival was unaffected in tandem-KD cells, as a consequence of strong transcriptional upregulation of MTs by infection and Sb V , overcoming the KD effect. Gene silencing of the metal transcription factor-1 (MTF-1) abrogated expression of MT1 and MT2-A genes, but not ZnT-1. Upon exposure to Sb V , intracellular survival of Leishmania in MTF-1 KD cells was significantly enhanced. Results from this study highlight the participation of macrophage MTs in Sb-dependent parasite killing.
参与药物抗细胞内病原体感染的药代动力学和药效学(PK/PD)的宿主细胞功能对药物疗效至关重要。在这项研究中，我们研究了巨噬细胞的外源解毒机制是否有助于在暴露于五价锑(sbv)时消除细胞内利什曼原虫。将皮肤利什曼病(CL)患者(n=6)的原代巨噬细胞体外暴露于L. V. panamensis感染和Sb V，并产生转录组。7个金属硫蛋白(MT)基因在前20个上调基因中，它们是重金属的强力清除剂和哺乳动物细胞机制的核心元素，用于外源性解毒。为了从功能上验证mt参与药物介导的细胞内利什曼原虫杀伤，在THP-1细胞中使用泛mt shRNA方法进行了MT2-A和MT1-E, MT1-F和MT1-X的串联敲低(KD)。在串联KD细胞中，寄生虫的存活不受影响，这是因为感染和Sb病毒强烈上调了mt的转录，克服了KD效应。金属转录因子-1 (MTF-1)的基因沉默会影响MT1和MT2-A基因的表达，但不会影响ZnT-1基因的表达。暴露于sbv后，利什曼原虫在MTF-1 KD细胞中的细胞内存活率显著提高。本研究结果强调巨噬细胞mt参与sb依赖性寄生虫的杀伤。
{"title":"Macrophage metallothioneins participate in the antileishmanial activity of antimonials","authors":"Deninson Alejandro Vargas, David J. Gregory, Roni Nitzan Koren, Dan Zilberstein, Ashton Trey Belew, Najib M. El-Sayed, María Adelaida Gómez","doi":"10.3389/fpara.2023.1242727","DOIUrl":"https://doi.org/10.3389/fpara.2023.1242727","url":null,"abstract":"Host cell functions that participate in the pharmacokinetics and pharmacodynamics (PK/PD) of drugs against intracellular pathogen infections are critical for drug efficacy. In this study, we investigated whether macrophage mechanisms of xenobiotic detoxification contribute to the elimination of intracellular Leishmania upon exposure to pentavalent antimonials (Sb V ). Primary macrophages from patients with cutaneous leishmaniasis (CL) (n=6) were exposed ex vivo to L. V. panamensis infection and Sb V , and transcriptomes were generated. Seven metallothionein (MT) genes, potent scavengers of heavy metals and central elements of the mammalian cell machinery for xenobiotic detoxification, were within the top 20 up-regulated genes. To functionally validate the participation of MTs in drug-mediated killing of intracellular Leishmania , tandem knockdown (KD) of MT2-A and MT1-E, MT1-F, and MT1-X was performed using a pan-MT shRNA approach in THP-1 cells. Parasite survival was unaffected in tandem-KD cells, as a consequence of strong transcriptional upregulation of MTs by infection and Sb V , overcoming the KD effect. Gene silencing of the metal transcription factor-1 (MTF-1) abrogated expression of MT1 and MT2-A genes, but not ZnT-1. Upon exposure to Sb V , intracellular survival of Leishmania in MTF-1 KD cells was significantly enhanced. Results from this study highlight the participation of macrophage MTs in Sb-dependent parasite killing.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135592227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-27DOI: 10.3389/fpara.2023.1249593
Paula Alfaro-Segura, Joby Robleto-Quesada, Víctor M. Montenegro-Hidalgo, Jose Arturo Molina-Mora, Gad Baneth, Guilherme G. Verocai, Roger I. Rodriguez-Vivas, Alicia Rojas
Spirocerca lupi is a parasitic nematode of domestic and wild canids of the world. This nematode induces esophageal spirocercosis and may eventually lead to carcinomas, aortic aneurisms, and death of the animal. Two genotypes of S. lupi have been described based on specimens from Europe, Asia, Africa, and Oceania, but no profound analysis has been conducted with S. lupi from the Americas. To study this, S. lupi specimens isolated from domestic dogs from Mexico, Costa Rica, and the United States, were molecularly characterized using 18S rDNA and cox 1 fragments. Bayesian inference (BI) phylogenetic trees, Templeton-Crandall-Sing (TCS) haplotype networks and Principal coordinate analysis on nucleotide distances were constructed for each locus separately. In addition, a phylogeographic study using a fragment of the cox 1 gene was used to infer the evolutionary history of the genus. BI cox 1 trees grouped S. lupi from the Americas in genotype 1, together with Israeli specimens, and showed a high nucleotide identity with those worms. In the TCS network, American specimens clustered next to Israeli S. lupi . Furthermore, the 18S rDNA gene fragment separated Costa Rican worms from African, Asian, and European specimens and other species of the family Spiruridae. Interestingly, the phylogeographic analysis suggested that the origin of S. vulpis was in Europe, and it later diverged into S. lupi that spread first to Africa, then to Asia and finally to the Americas. Therefore, we suggest that the worms from the American continent might have originated from Asia by dispersion of infected intermediate, paratenic or definitive hosts.
{"title":"Elucidating Spirocerca lupi spread in the Americas by using phylogenetic and phylogeographic analyses","authors":"Paula Alfaro-Segura, Joby Robleto-Quesada, Víctor M. Montenegro-Hidalgo, Jose Arturo Molina-Mora, Gad Baneth, Guilherme G. Verocai, Roger I. Rodriguez-Vivas, Alicia Rojas","doi":"10.3389/fpara.2023.1249593","DOIUrl":"https://doi.org/10.3389/fpara.2023.1249593","url":null,"abstract":"Spirocerca lupi is a parasitic nematode of domestic and wild canids of the world. This nematode induces esophageal spirocercosis and may eventually lead to carcinomas, aortic aneurisms, and death of the animal. Two genotypes of S. lupi have been described based on specimens from Europe, Asia, Africa, and Oceania, but no profound analysis has been conducted with S. lupi from the Americas. To study this, S. lupi specimens isolated from domestic dogs from Mexico, Costa Rica, and the United States, were molecularly characterized using 18S rDNA and cox 1 fragments. Bayesian inference (BI) phylogenetic trees, Templeton-Crandall-Sing (TCS) haplotype networks and Principal coordinate analysis on nucleotide distances were constructed for each locus separately. In addition, a phylogeographic study using a fragment of the cox 1 gene was used to infer the evolutionary history of the genus. BI cox 1 trees grouped S. lupi from the Americas in genotype 1, together with Israeli specimens, and showed a high nucleotide identity with those worms. In the TCS network, American specimens clustered next to Israeli S. lupi . Furthermore, the 18S rDNA gene fragment separated Costa Rican worms from African, Asian, and European specimens and other species of the family Spiruridae. Interestingly, the phylogeographic analysis suggested that the origin of S. vulpis was in Europe, and it later diverged into S. lupi that spread first to Africa, then to Asia and finally to the Americas. Therefore, we suggest that the worms from the American continent might have originated from Asia by dispersion of infected intermediate, paratenic or definitive hosts.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"29 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135580772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-26DOI: 10.3389/fpara.2023.1260224
Alejandro G. Schijman
Chagas disease (CD) caused by Trypanosoma cruzi remains a Neglected Tropical Disease with limited access to diagnosis and treatment, particularly for chronically infected patients. Clinical trials are underway to improve treatment using new drugs or different regimens, and Real-Time PCR is used to assess the parasitological response as a surrogate biomarker. However, PCR-based strategies have limitations due to the complex nature of T. cruzi infection. The parasite exhibits asynchronous replication, different strains and clones, and diverse tissue tropism, making it challenging to determine optimal timeline points for monitoring treatment response. This mini-review explores factors that affect PCR-based monitoring and summarizes the endpoints used in clinical trials for detecting treatment failure. Serial sampling and cumulative PCR results may improve sensitivity in detecting parasitemia and treatment failure in these trials.
{"title":"Unveiling challenges in real-time PCR strategies for detecting treatment failure: observations from clinical trials on chronic Chagas disease","authors":"Alejandro G. Schijman","doi":"10.3389/fpara.2023.1260224","DOIUrl":"https://doi.org/10.3389/fpara.2023.1260224","url":null,"abstract":"Chagas disease (CD) caused by Trypanosoma cruzi remains a Neglected Tropical Disease with limited access to diagnosis and treatment, particularly for chronically infected patients. Clinical trials are underway to improve treatment using new drugs or different regimens, and Real-Time PCR is used to assess the parasitological response as a surrogate biomarker. However, PCR-based strategies have limitations due to the complex nature of T. cruzi infection. The parasite exhibits asynchronous replication, different strains and clones, and diverse tissue tropism, making it challenging to determine optimal timeline points for monitoring treatment response. This mini-review explores factors that affect PCR-based monitoring and summarizes the endpoints used in clinical trials for detecting treatment failure. Serial sampling and cumulative PCR results may improve sensitivity in detecting parasitemia and treatment failure in these trials.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"64 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135719438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-26DOI: 10.3389/fpara.2023.1255848
Adeola Onasanya, Michel Bengtson, Ludo de Goeje, Jo van Engelen, Jan-Carel Diehl, Lisette van Lieshout
Introduction The INSPIRED project aims to develop inclusive Digital Optical Diagnostic Devices (DODDs) for schistosomiasis, to support disease management by enabling rapid diagnostic results, to improve efficient data management to guide decision-making and to provide healthcare workers with critical health information to facilitate follow-up action. Due to the non-availability of Target Product Profiles (TPPs) for guiding the development of digital diagnostics for schistosomiasis, we explored existing diagnostic TPPs. Methods Using a curated open access database (Notion database), we studied a selection of TPPs for diagnosing infectious diseases, focusing on specifications related to digital health products for Neglected Tropical Diseases (NTDs). Results Eighteen TPPs originating from 12 documents, covering 13 specific diseases, were selected and their characteristics were labeled and entered into the database. Further exploration of the database revealed several gaps, including a lack of stakeholder input, sustainability, and TPP availability. Other significant gaps related to digital health platform interconnectivity and data stewardship specifically in relation to digital diagnostics, including DODDs. Discussion These findings reflect two possible scenarios: (1) there is currently no need for digital diagnostic devices for schistosomiasis and, by extension for other NTDs; or (2) those needs are not yet covered by TPPs. Therefore, we recommend that digital health diagnostics are included in the use cases for schistosomiasis control and elimination, at least in the ideal/desirable scenario, as this will guide research and incentivize investment in digital health diagnostics for schistosomiasis.
{"title":"Developing inclusive digital health diagnostic for schistosomiasis: a need for guidance via target product profiles","authors":"Adeola Onasanya, Michel Bengtson, Ludo de Goeje, Jo van Engelen, Jan-Carel Diehl, Lisette van Lieshout","doi":"10.3389/fpara.2023.1255848","DOIUrl":"https://doi.org/10.3389/fpara.2023.1255848","url":null,"abstract":"Introduction The INSPIRED project aims to develop inclusive Digital Optical Diagnostic Devices (DODDs) for schistosomiasis, to support disease management by enabling rapid diagnostic results, to improve efficient data management to guide decision-making and to provide healthcare workers with critical health information to facilitate follow-up action. Due to the non-availability of Target Product Profiles (TPPs) for guiding the development of digital diagnostics for schistosomiasis, we explored existing diagnostic TPPs. Methods Using a curated open access database (Notion database), we studied a selection of TPPs for diagnosing infectious diseases, focusing on specifications related to digital health products for Neglected Tropical Diseases (NTDs). Results Eighteen TPPs originating from 12 documents, covering 13 specific diseases, were selected and their characteristics were labeled and entered into the database. Further exploration of the database revealed several gaps, including a lack of stakeholder input, sustainability, and TPP availability. Other significant gaps related to digital health platform interconnectivity and data stewardship specifically in relation to digital diagnostics, including DODDs. Discussion These findings reflect two possible scenarios: (1) there is currently no need for digital diagnostic devices for schistosomiasis and, by extension for other NTDs; or (2) those needs are not yet covered by TPPs. Therefore, we recommend that digital health diagnostics are included in the use cases for schistosomiasis control and elimination, at least in the ideal/desirable scenario, as this will guide research and incentivize investment in digital health diagnostics for schistosomiasis.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135718919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-22DOI: 10.3389/fpara.2023.1229467
Ulrike Grossmann, Maria-Luisa Rodriguez
Determining the success of antitrypanosomal therapy for Chagas disease is challenging, particularly in the chronic phase of the disease, because seropositivity persists for a long time after successful antitrypanosomal treatment and is known to be related to the duration of Trypanosoma cruzi infection. Seroconversion to negative by two or more conventional serologic tests is the currently accepted measure of efficacy, and studies suggest no significant change in seropositivity if left untreated. However, there is no guidance for industry on how to establish the effectiveness of drugs intended for the treatment of Chagas disease. Due to the lack of validated sensitive, specific, easy-to-use markers that allow early monitoring of the efficacy of antitrypanosomal treatment in an efficient manner, we used seroreduction measured by two conventional enzyme-linked immunosorbent assays in addition to the currently accepted criterion for what constitutes a cure, seroconversion to negative, as a surrogate parameter for efficacy in a Phase III pediatric trial with nifurtimox. The measures for confirmation of the antitrypanosomal efficacy of nifurtimox were discussed with US FDA. In this perspective article, we present our experiences obtained from a pediatric study on Chagas disease with an established drug using a surrogate efficacy parameter in addition to the established criterion for a cure.
{"title":"Chagas disease treatment efficacy markers: experiences from a Phase III study with nifurtimox in children","authors":"Ulrike Grossmann, Maria-Luisa Rodriguez","doi":"10.3389/fpara.2023.1229467","DOIUrl":"https://doi.org/10.3389/fpara.2023.1229467","url":null,"abstract":"Determining the success of antitrypanosomal therapy for Chagas disease is challenging, particularly in the chronic phase of the disease, because seropositivity persists for a long time after successful antitrypanosomal treatment and is known to be related to the duration of Trypanosoma cruzi infection. Seroconversion to negative by two or more conventional serologic tests is the currently accepted measure of efficacy, and studies suggest no significant change in seropositivity if left untreated. However, there is no guidance for industry on how to establish the effectiveness of drugs intended for the treatment of Chagas disease. Due to the lack of validated sensitive, specific, easy-to-use markers that allow early monitoring of the efficacy of antitrypanosomal treatment in an efficient manner, we used seroreduction measured by two conventional enzyme-linked immunosorbent assays in addition to the currently accepted criterion for what constitutes a cure, seroconversion to negative, as a surrogate parameter for efficacy in a Phase III pediatric trial with nifurtimox. The measures for confirmation of the antitrypanosomal efficacy of nifurtimox were discussed with US FDA. In this perspective article, we present our experiences obtained from a pediatric study on Chagas disease with an established drug using a surrogate efficacy parameter in addition to the established criterion for a cure.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"24 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136061720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-05DOI: 10.3389/fpara.2023.1235925
C. H. V. Moreira, A. Bierrenbach, C. Taconeli, Léa Campos de Oliveira-da Silva, Lewis F. Buss, Sheila M. Keating, E. Manuli, Noemia Barbosa Carvalho, C. Guastini, Sonia Bakkour Coco, J. Lindoso, Lucas Augusto Moyses Franco, Fabio Ghilardi, Flavia Cristina da Silva Sales, P. Contestable, C. Di Germanio, Michael P. Busch, E. Sabino
Evaluating the effectiveness of Chagas disease treatment poses challenges due to the lack of biomarkers for disease progression and therapeutic response. In this study, we aimed to assess the clearance of Trypanosoma cruzi (T. cruzi) parasites in a group of benznidazole (BNZ)-treated chronic Chagas disease patients using high-sensitivity quantitative PCR (qPCR) and track T. cruzi antibody levels through a semiquantitative chemiluminescent assay.A total of 102 T. cruzi seropositive patients with previous PCR-positive results were enrolled in the study. We collected samples 30 days before treatment (T-30d), on the day before initiating BNZ treatment (T0d), and at follow-up visits 60 days (T60d), 6 months (T6M), 12 months (T12M), and 36 months (T36M) after treatment initiation. Treatment efficacy was assessed by testing of serial samples using a target-capture qPCR assay specific to satellite T. cruzi DNA and the ORTHO T. cruzi ELISA Test System for antibody quantitation.Of the enrolled individuals, 87 completed at least 50% of the treatment course, and 86 had PCR results at follow-up visits T6M, T12M, and T36M. PCR results exhibited fluctuations before and after treatment, but levels were significantly lower post-treatment. Only 15 cases consistently tested PCR-negative across all post-treatment visits. Notably, nearly all participants demonstrated a declining antibody trajectory, with patients who tested PCR-negative at T36M exhibiting an earlier and more pronounced decline compared to PCR-positive cases at the same visit.Our study suggests that serial PCR results pose challenges in interpretation. In contrast, serial antibody levels may serve as an ancillary, or even a more reliable indicator of parasite decline following BNZ treatment. Monitoring antibody levels can provide valuable insights into the efficacy of treatment and the persistence of parasites in Chagas disease patients.
{"title":"Parasitemia and antibody response to benznidazole treatment in a cohort of patients with chronic Chagas disease","authors":"C. H. V. Moreira, A. Bierrenbach, C. Taconeli, Léa Campos de Oliveira-da Silva, Lewis F. Buss, Sheila M. Keating, E. Manuli, Noemia Barbosa Carvalho, C. Guastini, Sonia Bakkour Coco, J. Lindoso, Lucas Augusto Moyses Franco, Fabio Ghilardi, Flavia Cristina da Silva Sales, P. Contestable, C. Di Germanio, Michael P. Busch, E. Sabino","doi":"10.3389/fpara.2023.1235925","DOIUrl":"https://doi.org/10.3389/fpara.2023.1235925","url":null,"abstract":"Evaluating the effectiveness of Chagas disease treatment poses challenges due to the lack of biomarkers for disease progression and therapeutic response. In this study, we aimed to assess the clearance of Trypanosoma cruzi (T. cruzi) parasites in a group of benznidazole (BNZ)-treated chronic Chagas disease patients using high-sensitivity quantitative PCR (qPCR) and track T. cruzi antibody levels through a semiquantitative chemiluminescent assay.A total of 102 T. cruzi seropositive patients with previous PCR-positive results were enrolled in the study. We collected samples 30 days before treatment (T-30d), on the day before initiating BNZ treatment (T0d), and at follow-up visits 60 days (T60d), 6 months (T6M), 12 months (T12M), and 36 months (T36M) after treatment initiation. Treatment efficacy was assessed by testing of serial samples using a target-capture qPCR assay specific to satellite T. cruzi DNA and the ORTHO T. cruzi ELISA Test System for antibody quantitation.Of the enrolled individuals, 87 completed at least 50% of the treatment course, and 86 had PCR results at follow-up visits T6M, T12M, and T36M. PCR results exhibited fluctuations before and after treatment, but levels were significantly lower post-treatment. Only 15 cases consistently tested PCR-negative across all post-treatment visits. Notably, nearly all participants demonstrated a declining antibody trajectory, with patients who tested PCR-negative at T36M exhibiting an earlier and more pronounced decline compared to PCR-positive cases at the same visit.Our study suggests that serial PCR results pose challenges in interpretation. In contrast, serial antibody levels may serve as an ancillary, or even a more reliable indicator of parasite decline following BNZ treatment. Monitoring antibody levels can provide valuable insights into the efficacy of treatment and the persistence of parasites in Chagas disease patients.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44961581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-08DOI: 10.3389/fpara.2023.1223942
B. Rosa, D. Zarlenga, V. Fournet, E. Beshah, D. Hill, Alexander Zarlenga, Angela Yee, Xiaowu Liang, Adam D. Shandling, Amit Oberai, J. Urban, M. Mitreva
Soil transmitted nematodes are impediments to human health and agricultural production. Poor anthelmintic efficiencies, the emergence of resistant strains, and the persistence of infective stages highlight the need for more effective control strategies. Parasitic nematodes elicit a Th2-type immune response that most often is not protective. Vaccination has thus far been unsuccessful due to unrealized antigenic characters and unknown mechanisms that nematodes use to circumvent host immunity.Here, we used a genomics/proteomics approach (including immunoblot experiments from pigs infected with T. suis) to prioritize putative immunogenic excretory/secretory (E/S) proteins conserved across and specific to several gastrointestinal (GI) parasitic nematode species. A cocktail of five recombinant proteins optimized for conserved GI nematode targets was used immunize pigs and test for active antibody responses in both the serum and intestinal ileal fluid of immunized pigs. An antibody-protein array of putative immunogenic proteins was developed from a combined bioinformatic, experimental, and literature-based prioritization of homologous parasite proteins.Screening the array with sera and ileal fluid samples from immunized pigs suggested cross-reactivity among homologous proteins and a general activation of immunity. PCA clustering showed that the overall immune responses were altered by immunization, but no substantial changes were observed following direct worm challenge with either Ascaris suum or Trichuris suis.Proteins that activated immunity are potential antigens for immunization and the multi-omics phylum-spanning prioritization database that was created is a valuable resource for identifying target proteins in a wide array of different parasitic nematodes. This research strongly supports future studies using a computational, comparative genomics/proteomics approach to produce an effective parasite vaccine.
{"title":"Identification of broadly-conserved parasitic nematode proteins that activate immunity","authors":"B. Rosa, D. Zarlenga, V. Fournet, E. Beshah, D. Hill, Alexander Zarlenga, Angela Yee, Xiaowu Liang, Adam D. Shandling, Amit Oberai, J. Urban, M. Mitreva","doi":"10.3389/fpara.2023.1223942","DOIUrl":"https://doi.org/10.3389/fpara.2023.1223942","url":null,"abstract":"Soil transmitted nematodes are impediments to human health and agricultural production. Poor anthelmintic efficiencies, the emergence of resistant strains, and the persistence of infective stages highlight the need for more effective control strategies. Parasitic nematodes elicit a Th2-type immune response that most often is not protective. Vaccination has thus far been unsuccessful due to unrealized antigenic characters and unknown mechanisms that nematodes use to circumvent host immunity.Here, we used a genomics/proteomics approach (including immunoblot experiments from pigs infected with T. suis) to prioritize putative immunogenic excretory/secretory (E/S) proteins conserved across and specific to several gastrointestinal (GI) parasitic nematode species. A cocktail of five recombinant proteins optimized for conserved GI nematode targets was used immunize pigs and test for active antibody responses in both the serum and intestinal ileal fluid of immunized pigs. An antibody-protein array of putative immunogenic proteins was developed from a combined bioinformatic, experimental, and literature-based prioritization of homologous parasite proteins.Screening the array with sera and ileal fluid samples from immunized pigs suggested cross-reactivity among homologous proteins and a general activation of immunity. PCA clustering showed that the overall immune responses were altered by immunization, but no substantial changes were observed following direct worm challenge with either Ascaris suum or Trichuris suis.Proteins that activated immunity are potential antigens for immunization and the multi-omics phylum-spanning prioritization database that was created is a valuable resource for identifying target proteins in a wide array of different parasitic nematodes. This research strongly supports future studies using a computational, comparative genomics/proteomics approach to produce an effective parasite vaccine.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43601863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-27DOI: 10.3389/fpara.2023.1258999
M. V. Periago, R. Chuit
{"title":"Editorial: New opportunities for diagnosis and control of Chagas Disease to reach the 2030 goals for elimination","authors":"M. V. Periago, R. Chuit","doi":"10.3389/fpara.2023.1258999","DOIUrl":"https://doi.org/10.3389/fpara.2023.1258999","url":null,"abstract":"","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48503451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-24DOI: 10.3389/fpara.2023.1195646
R. Chuit, Laura Antonietti, R. N. Agüero, G. Varela, Oscar Daniel Mordini, Emilce Alemandri, M. Abril, M. Días, Z. Yadón, H. Pizzi, R. Pizzi
According to estimates by the World Health Organization, the infection and disease caused by the protozoan parasite Trypanosoma cruzi affects almost 6 million people, and more than 1 million suffer chagasic cardiomyopathy (Ch-CMP). It is estimated that 376,000 of these individuals live in Argentina. This study describes the characteristics and medical management of individuals with Ch-CMP in Argentina.This is a descriptive, retrospective, cross-sectional study on the diagnosis and clinical and therapeutic evaluation of patients with Ch-MCP using historical records collected from different medical institutions in the country between 1 January 2018 and 30 June 2021.During this period, 652 patients (mean age 61.2 years ± 12.9) were included, with women accounting for 60.3% of the sample. The diagnosis of cardiac insufficiency was 36.0% and 64.4% had arrhythmias. The most common cardiovascular risk factors detected were arterial hypertension (69.5%), smoking (56.6%), and diabetes (20.9%). Less than half of the subjects (45.4%) had been studied by electrocardiogram (ECG), chest X-ray, and echocardiogram. ECG studies showed conduction disorders (38.8%), left ventricular hypertrophy (28.1%), ventricular extrasystoles (22.0%), complete right bundle branch block (8.6%), and atrioventricular block (2.6%). According to the Kuschnir classification, 21.4% of the study subjects were in Grade 3.The patients included in the study had a similar clinical presentation and history of the disease to those published in other studies. When evaluating the medical practices, we found that patients were inadequately studied. Although it is difficult to estimate the fraction of the total number of patients represented by the present study, the study allowed us to establish that the care received by patients was not adequate.
{"title":"Diagnosis and management of chagasic cardiomyopathy patients in several institutions in Argentina","authors":"R. Chuit, Laura Antonietti, R. N. Agüero, G. Varela, Oscar Daniel Mordini, Emilce Alemandri, M. Abril, M. Días, Z. Yadón, H. Pizzi, R. Pizzi","doi":"10.3389/fpara.2023.1195646","DOIUrl":"https://doi.org/10.3389/fpara.2023.1195646","url":null,"abstract":"According to estimates by the World Health Organization, the infection and disease caused by the protozoan parasite Trypanosoma cruzi affects almost 6 million people, and more than 1 million suffer chagasic cardiomyopathy (Ch-CMP). It is estimated that 376,000 of these individuals live in Argentina. This study describes the characteristics and medical management of individuals with Ch-CMP in Argentina.This is a descriptive, retrospective, cross-sectional study on the diagnosis and clinical and therapeutic evaluation of patients with Ch-MCP using historical records collected from different medical institutions in the country between 1 January 2018 and 30 June 2021.During this period, 652 patients (mean age 61.2 years ± 12.9) were included, with women accounting for 60.3% of the sample. The diagnosis of cardiac insufficiency was 36.0% and 64.4% had arrhythmias. The most common cardiovascular risk factors detected were arterial hypertension (69.5%), smoking (56.6%), and diabetes (20.9%). Less than half of the subjects (45.4%) had been studied by electrocardiogram (ECG), chest X-ray, and echocardiogram. ECG studies showed conduction disorders (38.8%), left ventricular hypertrophy (28.1%), ventricular extrasystoles (22.0%), complete right bundle branch block (8.6%), and atrioventricular block (2.6%). According to the Kuschnir classification, 21.4% of the study subjects were in Grade 3.The patients included in the study had a similar clinical presentation and history of the disease to those published in other studies. When evaluating the medical practices, we found that patients were inadequately studied. Although it is difficult to estimate the fraction of the total number of patients represented by the present study, the study allowed us to establish that the care received by patients was not adequate.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49017695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-06DOI: 10.3389/fpara.2023.1214136
J. M. Lane, T. Brosschot, Dominique M Gatti, C. M. Gauthier, K. M. Lawrence, Victoria Pluzhnikova, L. Reynolds
Intestinal helminths have evolved an abundance of immunomodulatory mechanisms to ensure long-lived infections in mammalian hosts. To manipulate mammalian immune responses helminths can directly produce immunomodulatory molecules, but helminth infection can also elicit functional changes in the intestinal microbiome which can impact immune functioning. Here we examined how bile acids (BA)s, a group of host-produced, microbiota-modified immunomodulatory metabolites, were altered in abundance and composition during a murine small intestinal helminth infection. We found that murine helminth infection resulted in consistently reduced concentrations of specific taurine-conjugated primary BAs (T-α-MCA and T-CDCA) in the small intestinal luminal contents of mice. BA transporters facilitate the uptake of BAs from the small intestinal lumen, allowing BAs to engage with nuclear BA receptors, and helminth infected mice showed reduced expression of genes encoding basal BA transporters in the small intestine. Finally, we report that there is reduced signaling through the nuclear BA receptor FXR in both the proximal small intestine and ileum of mice during small intestinal helminth infection. Together, our data reveal disruptions to BA homeostasis and signaling in the small intestine during helminth infection. As BAs are known to impact many aspects of mucosal physiology and immunity, examining the functional consequences of BA disruptions during helminth infection will be an important avenue for future research.
{"title":"Chronic small intestinal helminth infection perturbs bile acid homeostasis and disrupts bile acid signaling in the murine small intestine","authors":"J. M. Lane, T. Brosschot, Dominique M Gatti, C. M. Gauthier, K. M. Lawrence, Victoria Pluzhnikova, L. Reynolds","doi":"10.3389/fpara.2023.1214136","DOIUrl":"https://doi.org/10.3389/fpara.2023.1214136","url":null,"abstract":"Intestinal helminths have evolved an abundance of immunomodulatory mechanisms to ensure long-lived infections in mammalian hosts. To manipulate mammalian immune responses helminths can directly produce immunomodulatory molecules, but helminth infection can also elicit functional changes in the intestinal microbiome which can impact immune functioning. Here we examined how bile acids (BA)s, a group of host-produced, microbiota-modified immunomodulatory metabolites, were altered in abundance and composition during a murine small intestinal helminth infection. We found that murine helminth infection resulted in consistently reduced concentrations of specific taurine-conjugated primary BAs (T-α-MCA and T-CDCA) in the small intestinal luminal contents of mice. BA transporters facilitate the uptake of BAs from the small intestinal lumen, allowing BAs to engage with nuclear BA receptors, and helminth infected mice showed reduced expression of genes encoding basal BA transporters in the small intestine. Finally, we report that there is reduced signaling through the nuclear BA receptor FXR in both the proximal small intestine and ileum of mice during small intestinal helminth infection. Together, our data reveal disruptions to BA homeostasis and signaling in the small intestine during helminth infection. As BAs are known to impact many aspects of mucosal physiology and immunity, examining the functional consequences of BA disruptions during helminth infection will be an important avenue for future research.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42359260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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