Frontiers in parasitology最新文献

{"title":"Reticulocyte Binding Protein Homologue 5 is a target of balancing selection in the Plasmodium falciparum population of Papua New Guinea","authors":"M. Naung, Elijah Martin, Wilson Wong, Z. Razook, Digjaya Utama, Andrew J. Guy, Shannon Takala Harrison, A. Cowman, E. Lin, Benson Kiniboro, M. Laman, Ivo Mueller, Alyssa E. Barry","doi":"10.3389/fpara.2023.1288867","DOIUrl":"https://doi.org/10.3389/fpara.2023.1288867","url":null,"abstract":"Plasmodium falciparum Reticulocyte Binding Protein Homologue (RH5), a leading malaria vaccine candidate, is essential for erythrocyte invasion by the parasite, interacting with the human host receptor, basigin. RH5 has a small number of polymorphisms relative to other blood-stage antigens, and in vitro studies have shown that vaccine-induced antibodies raised against RH5 are strain-transcending, however most studies investigating RH5 diversity have been done in Africa. Understanding the genetic diversity and evolution of malaria antigens in other regions is important for their validation as vaccine candidates. In this study the rh5 gene was sequenced in 677 samples from a longitudinal cohort of Papua New Guinean (PNG) children aged 1-3 years. Of 677 samples successfully sequenced, 566 were identified as independent infections (i.e. one of each pair of identical sequences within hosts were removed). A total of 14 non-synonymous polymorphisms were identified, eight that are ‘common’ in the population (minor allele frequency > 1%), with 44 haplotypes ranging in frequency from 1% to 21%. Modeling of common SNPs to the cryo-EM structure of the RH5/CyRPA/RIPR complex mapped them to the Basigin binding site and near the contact point of CyRPA. Tajima’s D analyses of the corresponding nucleotide sequences produced positive values indicating potential hotspots of balancing selection. We attempted to confirm whether these signals were due to immune selection by measuring the rate of polymorphism between independent infections within the same host, and the association with clinical symptoms, however, no such associations were identified. Together these results suggest that while there is evidence of balancing selection driving RH5 diversity in the PNG P. falciparum population, immune escape was not observed within the cohort of young children. Limited immunity and therefore low selective pressure may explain this result, alternatively other evolutionary forces may contribute to balancing selection at the RH5-BSG binding interface in PNG.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"44 27","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138946588","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}

{"title":"Limited value of current and new in silico predicted oocyst-specific proteins of Toxoplasma gondii for source-attributing serology","authors":"N. López-Ureña, R. Calero-Bernal, Břetislav Koudela, S. Cherchi, A. Possenti, Fabio Tosini, Sandra Klein, Carmen San Juan-Casero, Silvia Jara-Herrera, P. Jokelainen, J. Regidor-Cerrillo, L. Ortega-Mora, F. Spano, Frank Seeber, G. Álvarez‐García","doi":"10.3389/fpara.2023.1292322","DOIUrl":"https://doi.org/10.3389/fpara.2023.1292322","url":null,"abstract":"Toxoplasma gondii is a zoonotic parasite infecting all warm-blooded animals, including humans. The contribution of environmental contamination by T. gondii oocysts to infections is understudied. The aim of the current work was to explore T. gondii serology as a means of attributing the source of infection using a robust stepwise approach. We identified in silico thirty-two promising oocyst-specific antigens from T. gondii ´omics data, recombinantly expressed and purified them and validated whether serology based on these proteins could discriminate oocyst- from tissue cyst-driven experimental infections. For this, three well-characterized serum panels, sampled from 0 to 6 weeks post-infection, from pigs and sheep experimentally infected with T. gondii oocysts or tissue cysts, were used. Candidate proteins were initially screened by Western blot with sera from pigs or sheep, infected for different times, either with oocysts or tissue cysts, as well as non-infected animals. Only the recombinant proteins TgCCp5A and TgSR1 provoked seroconversion upon infection and appeared to discriminate between oocyst- and tissue cyst-driven infections with pig sera. They were subsequently used to develop an enzyme-linked immunosorbent assay test for pigs. Based on this assay and Western blot analyses, a lack of stage specificity and low antigenicity was observed with all pig sera. The same was true for proteins TgERP, TgSporoSAG, TgOWP1 and TgOWP8, previously described as source-attributing antigens, when analyzed using the whole panels of sera. We conclude that there is currently no antigen that allows the discrimination of T. gondii infections acquired from either oocysts or tissue cysts by serological tests. This work provides robust new knowledge that can inform further research and development toward source-attributing T. gondii serology.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139228232","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}

{"title":"Clinical use of molecular methods for Trypanosoma cruzi infection in endemic and non-endemic countries: Benefits, limitations and challenges","authors":"M. Pinazo, Colin J. Forsyth, Constanza Lopez-Albizu, M. Bisio, Adriana González-Martínez, Laura Bohorquez, Jimy Pinto, Israel Molina, A. Marchiol, Rafael Herazo, I. Galván, Tayná Marques, Fabiana Barreira, Juan Carlos Villar, Yanina Sguassero, Maria Soledad Santini, J. Altcheh, B. Alarcón de Noya, S. Sosa-Estani","doi":"10.3389/fpara.2023.1241154","DOIUrl":"https://doi.org/10.3389/fpara.2023.1241154","url":null,"abstract":"Trypanosoma cruzi infection is diagnosed by parasitological, molecular, and serological tests. Molecular methods based on DNA amplification provide a more sensitive alternative to classical parasitological techniques for detecting evidence of T. cruzi parasitemia, and are the preferred tests for congenital and oral transmission cases and parasite reactivation in chronically infected immunosuppressed individuals. In newborns at risk of vertical transmission, simplified diagnostic algorithms that provide timely results can reduce the high follow-up losses observed with current algorithms. Molecular methods have also proved useful for monitoring T. cruzi infection in solid organ transplantation recipients, regardless of host immune status, allowing parasite detection even before symptom manifestation. Furthermore, in the absence of other biomarkers and a practical test of cure, and given the limitations of serological methods, recent clinical guidelines have included polymerase chain reaction (PCR) to detect therapeutic failure after antiparasitic treatment in chronically infected adults. Increasing evidence supports the use of molecular tests in a clinical context, given the improved sensitivity and specificity of current assays – characteristics which largely depend on epidemiological factors and genetic and antigenic variability among T. cruzi strains. Further development and registration of commercial PCR kits will improve the use of molecular tests. We discuss the attributes of PCR and other molecular tests for clinical management in people with T. cruzi infection.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"6 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139252371","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}

{"title":"Longitudinal study of cross-reactive antigenemia in individuals with high Loa loa microfilarial density reveals promising biomarkers for distinguishing lymphatic filariasis from loiasis","authors":"Linda Djune-Yemeli, Marla I Hertz, H. Nana-Djeunga, Amy Rush, Petra Erdmann-Gilmore, Robert Sprung, J. Bopda, Reid Townsend, P. Netongo, Joseph Kamgno, Philip J. Budge","doi":"10.3389/fpara.2023.1292837","DOIUrl":"https://doi.org/10.3389/fpara.2023.1292837","url":null,"abstract":"Circulating Loa loa antigens are often detected in individuals with heavy L. loa infections by diagnostic tests for lymphatic filariasis (LF) caused by Wuchereria bancrofti. This is a major challenge to LF mapping and elimination efforts in loiasis co-endemic areas. However, it also provides an opportunity to identify antigen biomarkers for loiasis. To determine which L. loa antigens might be promising biomarkers for distinguishing true LF from loiasis, we screened for L. loa antigens in a group of individuals with heavy L. loa infections living in the Okola Health District of Cameroon. In this longitudinal study, participants were tested for cross-reactive antigenemia by filariasis test strip (FTS), ELISA, and western blot, and were monitored for FTS status at 6, 9, 12, and 15 months post-enrollment. We then identified specific circulating L. loa antigens by liquid chromatography-tandem mass spectrometry (LC-MS/MS) from baseline and 15-month plasma samples.Among 73 FTS-positive (FTS+) and 13 FTS-negative (FTS-) participants with high L. loa microfilarial loads, 83% maintained their FTS status over the course of the study, while 17% experienced at least one FTS conversion event (from FTS+ to FTS- or vice versa). Cross-reactive antigens were detected in both FTS+ and FTS- sera by western blot, and there was poor agreement in antigen detection by FTS, western blot, and ELISA methods. One protein family, a group of Nas-14 metalloproteases, was detected by LC MS/MS in >80% of tested samples, including FTS- samples. These data identify Nas-14 as a promising loiasis biomarker potentially capable of distinguishing loiasis from lymphatic filariasis.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139265868","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}

{"title":"Praziquantel activates a native cation current in <i>Schistosoma mansoni</i>.","authors":"Evgeny G Chulkov, Claudia M Rohr, Jonathan S Marchant","doi":"10.3389/fpara.2023.1285177","DOIUrl":"10.3389/fpara.2023.1285177","url":null,"abstract":"<p><strong>Introduction: </strong>Praziquantel (PZQ), an anthelmintic drug discovered in the 1970s, is still used to treat schistosomiasis and various other infections caused by parasitic flatworms. PZQ causes a triad of phenotypic effects on schistosome worms - rapid depolarization, muscle contraction, and damage throughout the worm tegument. The molecular target mediating these effects has been intimated as a Ca²⁺-permeable ion channel, but native currents evoked by PZQ have not been reported in any schistosome cell type. The properties of the endogenous PZQ activated conductance therefore remain unknown.</p><p><strong>Methods: </strong>Here, invasive electrophysiology was used to probe for responses to PZQ from different locales in a living schistosome worm.</p><p><strong>Results and discussion: </strong>No direct response was seen in tegument-derived vesicles, or from the sub-tegumental muscle layer despite the presence of voltage-operated currents. However, PZQ rapidly triggered a sustained, non-selective cation current in recordings from neuronal tissue, targeting both the anterior ganglion and the main longitudinal nerve cord. The biophysical signature of this PZQ-evoked current resolved at single channel resolution matched that of a transient receptor potential ion channel named TRPM_PZQ, recently proposed as the molecular target of PZQ. The endogenous PZQ-evoked current was also inhibited by a validated TRPM_PZQ antagonist. PZQ therefore is a neuroactive anthelmintic, causing a sustained depolarization through ion channels with the characteristics of TRPM_PZQ.</p>","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"2 ","pages":"1285177"},"PeriodicalIF":0.0,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143017495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An essential Trypanosoma brucei protein kinase: a functional analysis of regulation and the identification of inhibitors","authors":"Marilyn Parsons, Ben Parsons, Marissa Dean, Amy E. DeRocher, Zeba Islam, Dustin J. Maly, Bryan C. Jensen","doi":"10.3389/fpara.2023.1272378","DOIUrl":"https://doi.org/10.3389/fpara.2023.1272378","url":null,"abstract":"Introduction The protein serine/threonine kinase AEK1 is essential in the pathogenic stage of Trypanosoma brucei, the causative agent of African trypanosomiasis. AEK1 is a member of the AGC protein kinase family, although it is not closely related to a specific human AGC kinase. Our previous chemical genetic studies showed that targeted inhibition of AEK1 in parasites expressing analog-sensitive AEK1 blocked parasite growth and enhanced survival of infected mice. Methods To further validate AEK1 as a drug target, we used the chemical genetic system to determine the effect of a 24 hour loss of AEK1 activity on cell viability at the clonal level. A panel of 429 protein kinase inhibitors were screened against the wild-type protein for binding, using time-resolved fluorescence energy transfer (TR-FRET). The role of phosphorylation sites and motifs was probed by determining whether expression of proteins harboring mutations in these sequences could rescue AEK1 conditional knockout parasites. To determine the effect that mutations in the phosphosites have on the kinase activity of cellular AEK1 we compared the in vitro kinase activity of mutant and wild-type proteins immunoprecipitated from parasite lysates using the exogenous substrate MBP. Finally, the tagged AEK1 protein was localized by deconvolution microscopy. Results After a 24 hour exposure to an AEK1 inhibitory analog in the chemical genetic system, less than five percent of the remaining live cells can clonally expand, further validating AEK1 as a drug target. In the AEK1 inhibitor screening assay, we identified 17 hit compounds. Complementation studies showed that of the two known phosphorylation sites in the activation loop; mutation of one abolished function while mutation of the other had no discernable effect. Mutation of the other two AEK1 phosphosites gave intermediate phenotypes. Mutations in either the hydrophobic motif at the C-terminus of the protein or in the region of AEK1 predicted to bind the hydrophobic motif were also required for function. All parasites with defective AEK1 showed reduced proliferation and defects in cytokinesis, although the tested mutations differed in terms of the extent of cell death. Kinase activity of immunoprecipitated AEK1 phosphosite mutants largely paralleled the effects seen in complementation studies, although the mutation of the phosphosite adjacent to the hydrophobic motif had a greater impact on activity than predicted by the complementation studies. AEK1 was localized to cytoplasmic puncta distinct from glycosomes and acidocalcisomes. Discussion The rapid loss of viability of cells inhibited for AEK1 supports the idea that a short course of treatment that target AEK1 may be sufficient for treatment of people or animals infected with T. brucei. Key regulatory elements between AEK1 and its closest mammalian homolog appear to be largely conserved despite the vast evolutionary distance between mammals and T. brucei. The presence of AEK1 in cytopla","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"27 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134993001","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}

{"title":"Real-time PCR for diagnosing and monitoring treatment effect of Strongyloides stercoralis infection in a non-endemic setting","authors":"Linda J. Wammes, Suzanne A. V. van Asten, Lisette van Lieshout, Els Wessels, Jaco J. Verweij","doi":"10.3389/fpara.2023.1277372","DOIUrl":"https://doi.org/10.3389/fpara.2023.1277372","url":null,"abstract":"Word count: 211 Introduction The laboratory diagnosis of Strongyloides stercoralis is notoriously difficult. Microscopic diagnosis, even using concentration techniques and repeated sampling, is known to lack sensitivity. Serology depending on the type of test used have shown adequate sensitivity but specificity is generally low. In the present study the performance of S. stercoralis real-time PCR as a routine diagnostic test is evaluated in two different non-endemic settings. Methods Strongyloides stercoralis real-time PCR, serology, and microscopy results with available clinical and anamnestic data were extracted from the laboratory information management systems between August 2005 and December 2022. Results A total of 19179 Strongyloides stercoralis PCR results were retrieved in which in 149 specimens from 103 patients S. stercoralisspecific DNA was detected. Microscopy revealed S. stercoralis larvae in 19 of 36 (53%) PCR positive patients. Whereas serology tested positive in 70 of 74 (94.6%) of all available serum samples of S. stercoralis PCR positive patients and in 61 of 63 (96.8%) when limited to serology results within 6 weeks around the primary PCR-positive specimen. In 79% (38 of 48 patients) the first follow-up feces sample tested PCR negative. Discussion Strongyloides stercoralis real-time PCR showed a valuable diagnostic tool for the detecting and monitoring of S. stercoralis infections and detected additional cases compared to microscopy and serology.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"28 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136312233","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}

{"title":"Identification of biomarker candidates for filarial parasite infections by analysis of extracellular vesicles","authors":"Devyn Yates, Lucia S. Di Maggio, Bruce A. Rosa, Robert W. Sprung, Petra Erdmann-Gilmore, R. Reid Townsend, Philip J. Budge, Joseph Kamgno, Makedonka Mitreva, Gary J. Weil, Peter U. Fischer","doi":"10.3389/fpara.2023.1281092","DOIUrl":"https://doi.org/10.3389/fpara.2023.1281092","url":null,"abstract":"Background Improved diagnostic tools are needed for detecting active filarial infections in humans. Tests are available that detect adult W. bancrofti circulating filarial antigen, but there are no sensitive and specific biomarker tests for brugian filariasis or loiasis. Here we explored whether extracellular vesicles released by filarial parasites contain diagnostic biomarker candidates. Methods Vesicles were isolated using VN96-affinity purification from supernatants of short-term in vitro cultured B. malayi microfilariae (Mf) and analyzed by mass spectrometry (Bruker timsTOF). Parasite-specific proteins were identified by bioinformatic analysis and a protein was called present if supported by ≥ 2 spectra. After validation with cultures parasites, this approach was then used to analyze vesicles isolated from plasma of animals infected with B. malayi and from humans with heavy Loa loa infections. Results Vesicles from Mf cultures contained more than 300 B. malayi proteins with high consistency across biological replicates. These included the known Mf excretory antigen BmR1 (AF225296). Over 150 B. malayi proteins were detected in vesicles isolated from plasma samples from two infected animals. Vesicles isolated from plasma from 10 persons with high L. loa Mf densities contained consistently 21 proteins, 9 of them were supported by at least 5 unique peptides and 7 with spectral counts above 10. The protein EN70_10600 (an orthologue of the B. malayi antigen BmR1, GenBank AF225296) was detected in all 10 samples with a total count of 91 spectra and a paralogue (EN70_10598) was detected in 6 samples with a total of 44 spectra. Discussion Extracellular vesicles released by filarial parasites in vitro and in vivo contain parasite proteins which can be reliably detected by mass spectrometry. This research provides the foundation to develop antigen detection assays to improve diagnosis of active filarial infections in humans.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"21 12","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135366507","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}

{"title":"Myeloid- and epithelial-derived RELMα contribute to tissue repair following lung helminth infection","authors":"Stefanie N. Sveiven, Sang Yong Kim, Valeria Barrientos, Jiang Li, Jennell Jennett, Samuel Asiedu, Kyle Anesko, Tara M. Nordgren, Meera G. Nair","doi":"10.3389/fpara.2023.1242866","DOIUrl":"https://doi.org/10.3389/fpara.2023.1242866","url":null,"abstract":"Soil-transmitted helminth (STH) infections impact billions of individuals globally; however, there is a need to clarify the long-term impacts of these infections on pulmonary health owing to their transient migration and subsequent damage to the lungs. In mouse models of these infections using Nippostrongylus brasiliensis , lung pathology persists at later time points post single infection. These studies also indicate the persistent transcriptional expression of resistin-like molecule α (RELMα), an immunomodulatory protein induced in type 2 immunity and alternatively activated macrophages. Using constitutive and tamoxifen-inducible cell-specific RELMα knockout mouse strains, we identified that epithelial- and myeloid-derived RELMα protein remained elevated at 30 days post infection and altered the immune cell signature and gene expression in lung compartments. Histopathological assessment of alveolar damage revealed a role for RELMα in tissue repair, suggesting the importance of sustained RELMα expression for lung recovery from helminth infection. Acellular three-dimensional (3D) lung scaffolds were prepared from the lungs of wild-type (WT), RELMα KO-naive, or 30 days post N. brasiliensis -infected mice to assess their ability to support epithelial cell growth. N. brasiliensis infection significantly altered the scaffold and impaired epithelial cell growth and metabolic activity, especially in the RELMα KO scaffolds. These findings underscore a need to identify the long-term impacts of helminth infection on human pulmonary disease, particularly as alveolar destruction can develop into chronic obstructive pulmonary disease (COPD), which remains among the top global causes of death. Translation of these findings to human protein resistin, with sequence homology to RELMα therapeutic opportunities in lung repair.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"4 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135918091","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}

{"title":"Immunomodulatory proteins from hookworms reduce cardiac inflammation and modulate regulatory responses in a mouse model of chronic Trypanosoma cruzi infection","authors":"Kathryn M. Jones, Bin Zhan, Keenan J. Ernste, Maria Jose Villar, Nalini Bisht, Duc Nguyen, Li-Yen Chang, Cristina Poveda, Gonteria J. Robinson, Akshar J. Trivedi, Colby J. Hofferek, William K. Decker, Vanaja Konduri","doi":"10.3389/fpara.2023.1244604","DOIUrl":"https://doi.org/10.3389/fpara.2023.1244604","url":null,"abstract":"Introduction Hookworms are parasitic helminths that secrete a variety of proteins that induce anti-inflammatory immune responses, stimulating increased CD4+Foxp3+ regulatory T cells and IL-10 production. Hookworm-derived recombinant proteins AIP-1 and AIP-2 have been shown to reduce inflammation in mouse models of inflammatory bowel disease and inflammatory airway disease by inducing CD4+Foxp3+ cells and IL-10 production. In contrast, chronic infection with the protozoal parasite Trypanosoma cruzi , the causative agent of Chagas disease, leads to chronic inflammation in tissues. Persistence of the parasites in tissues drives chronic low-grade inflammation, with increased infiltration of inflammatory cells into the heart, accompanied by increased production of inflammatory cytokines. There are no current antiparasitic drugs that effectively reduce or prevent chronic myocarditis caused by the onset of Chagas disease, thus new therapies are urgently needed. Therefore, the impact of AIP-1 and AIP-2 on myocarditis was investigated in a mouse model of chronic T. cruzi infection. Methods Female BALB/c mice infected with bioluminescent T. cruzi H1 strain trypomastigotes for 70 days were treated once daily for 7 days with 1mg/kg AIP-1 or AIP-2 protein by intraperitoneal injection. Control mice were left untreated or treated once daily for 14 days with 25mg/kg aspirin in drinking water. At 84 days of infection, splenocytes, cardiac tissue and serum were collected for evaluation. Results Treatment with both AIP-1 and AIP-2 proteins significantly reduced cardiac cellular infiltration, and reduced cardiac levels of IFNγ, IL-6 and IL-2. AIP-2 treatment reduced cardiac expression of COX-2. Further, while incubation with AIP-1 and AIP-2 proteins did not induce a significant upregulation of an immunoregulatory phenotype in dendritic cells (DC), there was a modest upregulation of CD11c+CD11b+MHCII+SIRPα+ expression, suggesting a regulatory phenotype. Ex-vivo stimulation of splenocytes from the treatment groups with AIP-1 loaded DC induced reduced levels of cytotoxic and pro-inflammatory T cells, stimulation with AIP-2 loaded DC specifically induced enhanced levels of CD4+CD25+Foxp3+ regulatory T cells among treatment groups. Discussion All in vivo and in vitro results demonstrate that hookworm-derived AIP-1 and AIP-2 proteins reduce T. cruzi induced cardiac inflammation, possibly through multiple anti-inflammatory mechanisms.","PeriodicalId":73098,"journal":{"name":"Frontiers in parasitology","volume":"56 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135968674","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}