ORCID Profile
0000-0001-9572-3436
Current Organisation
Washington University in St. Louis School of Medicine
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Publisher: Springer Science and Business Media LLC
Date: 28-08-2004
DOI: 10.1007/S00438-004-1054-0
Abstract: Plant-parasitic nematodes are important and cosmopolitan pathogens of crops. Here, we describe the generation and analysis of 1928 expressed sequence tags (ESTs) of a splice-leader 1 (SL1) library from mixed life stages of the root-lesion nematode Pratylenchus penetrans. The ESTs were grouped into 420 clusters and classified by function using the Gene Ontology (GO) hierarchy and the Kyoto KEGG database. Approximately 80% of all translated clusters show homology to Caenorhabditis elegans proteins, and 37% of the C. elegans gene homologs had confirmed phenotypes as assessed by RNA interference tests. Use of an SL1-PCR approach, while ensuring the cloning of the 5' ends of mRNAs, has demonstrated bias toward short transcripts. Putative nematode-specific and Pratylenchus -specific genes were identified, and their implications for nematode control strategies are discussed.
Publisher: Springer Science and Business Media LLC
Date: 06-2012
DOI: 10.1038/NATURE11234
Publisher: Proceedings of the National Academy of Sciences
Date: 29-08-2022
Abstract: Parasitic helminth infections, while a major cause of neglected tropical disease burden, negatively correlate with the incidence of immune-mediated inflammatory diseases such as inflammatory bowel diseases (IBD). To evade expulsion, helminths have developed sophisticated mechanisms to regulate their host’s immune responses. Controlled experimental human helminth infections have been assessed clinically for treating inflammatory conditions however, such a radical therapeutic modality has challenges. An alternative approach is to harness the immunomodulatory properties within the worm’s excretory–secretory (ES) complement, its secretome. Here, we report a biologics discovery and validation pipeline to generate and screen in vivo a recombinant cell-free secretome library of helminth-derived immunomodulatory proteins. We successfully expressed 78 recombinant ES proteins from gastrointestinal hookworms and screened the crude in vitro translation reactions for anti-IBD properties in a mouse model of acute colitis. After statistical filtering and ranking, 20 proteins conferred significant protection against various parameters of colitis. Lead candidates from distinct protein families, including annexins, transthyretins, nematode-specific retinol-binding proteins, and SCP/TAPS were identified. Representative proteins were produced in mammalian cells and further validated, including ex vivo suppression of inflammatory cytokine secretion by T cells from IBD patient colon biopsies. Proteins identified herein offer promise as novel, safe, and mechanistically differentiated biologics for treating the globally increasing burden of inflammatory diseases.
Publisher: Elsevier BV
Date: 11-2015
Publisher: Oxford University Press (OUP)
Date: 03-05-2014
Publisher: Springer Science and Business Media LLC
Date: 22-02-2013
Abstract: Cooperia oncophora and Ostertagia ostertagi are among the most important gastrointestinal nematodes of cattle worldwide. The economic losses caused by these parasites are on the order of hundreds of millions of dollars per year. Conventional treatment of these parasites is through anthelmintic drugs however, as resistance to anthelmintics increases, overall effectiveness has begun decreasing. New methods of control and alternative drug targets are necessary. In-depth analysis of transcriptomic data can help provide these targets. The assembly of 8.7 million and 11 million sequences from C. oncophora and O. ostertagi , respectively, resulted in 29,900 and 34,792 transcripts. Among these, 69% and 73% of the predicted peptides encoded by C. oncophora and O. ostertagi had homologues in other nematodes. Approximately 21% and 24% were constitutively expressed in both species, respectively however, the numbers of transcripts that were stage specific were much smaller (~1% of the transcripts expressed in a stage). Approximately 21% of the transcripts in C. oncophora and 22% in O. ostertagi were up-regulated in a particular stage. Functional molecular signatures were detected for 46% and 35% of the transcripts in C. oncophora and O. ostertagi , respectively. More in-depth examinations of the most prevalent domains led to knowledge of gene expression changes between the free-living (egg, L1, L2 and L3 sheathed) and parasitic (L3 exsheathed, L4, and adult) stages. Domains previously implicated in growth and development such as chromo domains and the MADF domain tended to dominate in the free-living stages. In contrast, domains potentially involved in feeding such as the zinc finger and CAP domains dominated in the parasitic stages. Pathway analyses showed significant associations between life-cycle stages and peptides involved in energy metabolism in O. ostertagi whereas metabolism of cofactors and vitamins were specifically up-regulated in the parasitic stages of C. oncophora. Substantial differences were observed also between Gene Ontology terms associated with free-living and parasitic stages. This study characterized transcriptomes from multiple life stages from both C. oncophora and O. ostertagi. These data represent an important resource for studying these parasites. The results of this study show distinct differences in the genes involved in the free-living and parasitic life cycle stages. The data produced will enable better annotation of the upcoming genome sequences and will allow future comparative analyses of the biology, evolution and adaptation to parasitism in nematodes.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2013
Publisher: Springer Science and Business Media LLC
Date: 09-2008
DOI: 10.1038/NATURE07253
Publisher: Elsevier BV
Date: 10-2005
DOI: 10.1016/J.TIG.2005.08.003
Abstract: Recent transcriptome and genome projects have dramatically expanded the biological data available across the phylum Nematoda. Here we summarize analyses of these sequences, which have revealed multiple unexpected results. Despite a uniform body plan, nematodes are more erse at the molecular level than was previously recognized, with many species- and group-specific novel genes. In the genus Caenorhabditis, changes in chromosome arrangement, particularly local inversions, are also rapid, with breakpoints occurring at 50-fold the rate in vertebrates. Tylenchid plant parasitic nematode genomes contain several genes closely related to genes in bacteria, implicating horizontal gene transfer events in the origins of plant parasitism. Functional genomics techniques are also moving from Caenorhabditis elegans to application throughout the phylum. Soon, eight more draft nematode genome sequences will be available. This unique resource will underpin both molecular understanding of these most abundant metazoan organisms and aid in the examination of the dynamics of genome evolution in animals.
Publisher: Public Library of Science (PLoS)
Date: 27-09-2007
Publisher: Public Library of Science (PLoS)
Date: 26-05-2020
Publisher: Elsevier BV
Date: 12-2010
Publisher: Elsevier BV
Date: 10-2014
Publisher: Springer Science and Business Media LLC
Date: 09-11-2016
DOI: 10.1038/SREP36797
Abstract: A reduced ersity of the gastrointestinal commensal microbiota is associated with the development of several inflammatory diseases. Recent reports in humans and animal models have demonstrated the beneficial therapeutic effects of infections by parasitic worms (helminths) in some inflammatory disorders, such as inflammatory bowel disease (IBD) and coeliac disease (CeD). Interestingly, these studies have described how helminths may alter the intestinal microbiota, potentially representing a mechanism by which they regulate inflammation. However, for practical reasons, these reports have primarily analysed the faecal microbiota. In the present investigation, we have assessed, for the first time, the changes in the microbiota at the site of infection by a parasitic helminth (hookworm) and gluten-dependent inflammation in humans with CeD using biopsy tissue from the duodenum. Hookworm infection and gluten exposure were associated with an increased abundance of species within the Bacteroides phylum, as well as increases in the richness and ersity of the tissue-resident microbiota within the intestine, results that are consistent with previous reports using other helminth species in humans and animal models. Hence, this may represent a mechanism by which parasitic helminths may restore intestinal immune homeostasis and exert a therapeutic benefit in CeD, and potentially other inflammatory disorders.
Publisher: Springer Science and Business Media LLC
Date: 05-11-2018
Publisher: Cold Spring Harbor Laboratory
Date: 22-05-2022
DOI: 10.1101/2022.05.22.492965
Abstract: Intricate molecular communication between the schistosome (flatworms) and its mammalian host, as well as between paired male and female schistosomes has shaped the secreted proteome of these flatworms. Whereas the schistosome egg is responsible for the disease manifestations of chronic schistosomiasis, the long lived, adult female and male stages also release mediators that facilitate their long-lived intra-vascular existence in a hostile niche where they are bathed in immune cells and effector molecules. However, despite their importance, no studies have focused on analysing the excretory/secretory products (ESPs) from adult schistosomes. Herein, ESPs from cultured Schistosoma mansoni male or female adult worms were identified, quantified, compared and contrasted using a label-free proteomic approach. Approximately 1,000 proteins were identified, from which almost 800 could be finally quantified. Considering the proteins uniquely identified and proteins with a significantly regulated expression pattern in male or female flukes, a total of 370 and 140 proteins were more abundantly secreted by males and females, respectively. Using functional analysis networks showing the gene ontology terms and KEGG pathways with the highest significance, we observed that male schistosomes secrete proteins related to carbohydrate metabolism, cytoskeletal organisation more abundantly than females, while female worms secreted more hydrolases and proteins involved in cellular homeostasis than males. This analysis doubles the number of previously reported ESPs from S. mansoni , contributing to a better understanding of the host-parasite dynamic interactions. Furthermore, these findings expand potential vaccine and diagnostic candidates for this neglected tropical disease pathogen, which will enable deeper understanding of the molecular communication critical to parasitism.
Publisher: Elsevier BV
Date: 10-2014
Publisher: Springer Science and Business Media LLC
Date: 09-02-2016
DOI: 10.1038/SREP20316
Abstract: The bovine lungworm, Dictyocaulus viviparus (order Strongylida), is an important parasite of livestock that causes substantial economic and production losses worldwide. Here we report the draft genome, variome and developmental transcriptome of D. viviparus . The genome (161 Mb) is smaller than those of related bursate nematodes and encodes fewer proteins (14,171 total). In the first genome-wide assessment of genomic variation in any parasitic nematode, we found a high degree of sequence variability in proteins predicted to be involved host-parasite interactions. Next, we used extensive RNA sequence data to track gene transcription across the life cycle of D. viviparus and identified genes that might be important in nematode development and parasitism. Finally, we predicted genes that could be vital in host-parasite interactions, genes that could serve as drug targets and putative RNAi effectors with a view to developing functional genomic tools. This extensive, well-curated dataset should provide a basis for developing new anthelmintics, vaccines and improved diagnostic tests and serve as a platform for future investigations of drug resistance and epidemiology of the bovine lungworm and related nematodes.
Publisher: MDPI AG
Date: 24-07-2023
DOI: 10.3390/PATHOGENS12070971
Abstract: Onchocerciasis is a neglected tropical disease targeted for elimination using ivermectin mass administration. Ivermectin kills the microfilariae and temporarily arrests microfilariae production by the macrofilariae. We genotyped 436 microfilariae from 10 people each in Ituri, Democratic Republic of the Congo (DRC), and Maridi County, South Sudan, collected before and 4–5 months after ivermectin treatment. Population genetic analyses identified 52 and 103 mitochondrial DNA haplotypes among the microfilariae from DRC and South Sudan, respectively, with few haplotypes shared between people. The percentage of genotype-based correct assignment to person within DRC was ~88% and within South Sudan ~64%. Rarefaction and extrapolation analysis showed that the genetic ersity in DRC, and even more so in South Sudan, was captured incompletely. The results indicate that the per-person adult worm burden is likely higher in South Sudan than DRC. Analyses of haplotype data from a subs le (n = 4) did not discriminate genetically between pre- and post-treatment microfilariae, confirming that post-treatment microfilariae are not the result of new infections. With appropriate s ling, mitochondrial haplotype analysis could help monitor changes in the number of macrofilariae in a population as a result of treatment, identify cases of potential treatment failure, and detect new infections as an indicator of continuing transmission.
Publisher: Springer Science and Business Media LLC
Date: 2007
Publisher: MDPI AG
Date: 12-09-2023
Publisher: Oxford University Press (OUP)
Date: 2016
Abstract: Paragonimiasis caused by lung flukes (genus Paragonimus) is a neglected disease occurring in Asia, Africa and the Americas. The genus is species-rich, ancient and widespread. Genetic ersity is likely to be considerable, but investigation of this remains confined to a few populations of a few species. In recent years, studies of genetic ersity have moved from isoenzyme analysis to molecular phylogenetic analysis based on selected DNA sequences. The former offered better resolution of questions relating to allelic ersity and gene flow, whereas the latter is more suitable for questions relating to molecular taxonomy and phylogeny. A picture is emerging of a highly erse taxon of parasites, with the greatest ersity found in eastern and southern Asia where ongoing speciation might be indicated by the presence of several species complexes. Diversity of lung flukes in Africa and the Americas is very poorly s led. Functional molecules that might be of value for immunodiagnosis, or as targets for medical intervention, are of great interest. Characterisation of these from Paragonimus species has been ongoing for a number of years. However, the imminent release of genomic and transcriptomic data for several species of Paragonimus will dramatically increase the rate of discovery of such molecules, and illuminate their ersity within and between species.
Publisher: Springer Science and Business Media LLC
Date: 2010
Publisher: Elsevier BV
Date: 03-2014
Publisher: Public Library of Science (PLoS)
Date: 07-06-2011
Publisher: Public Library of Science (PLoS)
Date: 11-05-2010
Publisher: Springer Science and Business Media LLC
Date: 18-09-2015
DOI: 10.1038/SREP13797
Abstract: The intestinal microbiota plays a critical role in the development of the immune system. Recent investigations have highlighted the potential of helminth therapy for treating a range of inflammatory disorders, including celiac disease (CeD) however, the mechanisms by which helminths modulate the immune response of the human host and ameliorate CeD pathology are unknown. In this study, we investigated the potential role of alterations in the human gut microbiota in helminth-mediated suppression of an inflammatory disease. We assessed the qualitative and quantitative changes in the microbiota of human volunteers with CeD prior to and following infection with human hookworms and following challenge with escalating doses of dietary gluten. Experimental hookworm infection of the trial subjects resulted in maintenance of the composition of the intestinal flora, even after a moderate gluten challenge. Notably, we observed a significant increase in microbial species richness over the course of the trial, which could represent a potential mechanism by which hookworms can regulate gluten-induced inflammation and maintain intestinal immune homeostasis.
Publisher: Elsevier BV
Date: 05-2011
Publisher: Oxford University Press (OUP)
Date: 03-08-2010
DOI: 10.1093/NAR/GKQ667
Publisher: Public Library of Science (PLoS)
Date: 22-05-2013
Publisher: Springer Science and Business Media LLC
Date: 28-01-2009
Abstract: Amino acid insertions and deletions in proteins are considered relatively rare events, and their associations with the evolution and adaptation of organisms are not yet understood. In this study, we undertook a systematic analysis of over 214,000 polypeptides from 32 nematode species and identified insertions and deletions unique to nematode proteins in more than 1000 families and provided indirect evidence that these alterations are linked to the evolution and adaptation of nematodes. Amino acid alterations in sequences of nematodes were identified by comparison with homologous sequences from a wide range of eukaryotic (metzoan) organisms. This comparison revealed that the proteins inferred from transcriptomic datasets for nematodes contained more deletions than insertions, and that the deletions tended to be larger in length than insertions, indicating a decreased size of the transcriptome of nematodes compared with other organisms. The present findings showed that this reduction is more pronounced in parasitic nematodes compared with the free-living nematodes of the genus Caenorhabditis . Consistent with a requirement for conservation in proteins involved in the processing of genetic information, fewer insertions and deletions were detected in such proteins. On the other hand, more insertions and deletions were recorded for proteins inferred to be involved in the endocrine and immune systems, suggesting a link with adaptation. Similarly, proteins involved in multiple cellular pathways tended to display more deletions and insertions than those involved in a single pathway. The number of insertions and deletions shared by a range of plant parasitic nematodes were higher for proteins involved in lipid metabolism and electron transport compared with other nematodes, suggesting an association between metabolic adaptation and parasitism in plant hosts. We also identified three sizable deletions from proteins found to be specific to and shared by parasitic nematodes, which, given their uniqueness, might serve as target candidates for drug design. This study illustrates the significance of using comparative genomics approaches to identify molecular elements unique to parasitic nematodes, which have adapted to a particular host organism and mode of existence during evolution. While the focus of this study was on nematodes, the approach has applicability to a wide range of other groups of organisms.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2015
Publisher: Springer Science and Business Media LLC
Date: 05-2008
DOI: 10.1038/NATURE06936
Publisher: Springer Science and Business Media LLC
Date: 28-12-2005
DOI: 10.1007/S00436-005-0029-3
Abstract: The beet cyst nematode Heterodera schachtii is an important pathogen worldwide, but its molecular characterization has been limited to studying in idual genes of interest. We undertook a high-throughput genomic approach and drastically increased the number of available sequences for this parasite. A total of 2,662 expressed sequence tags were grouped into 1,212 clusters representing a nonredundant catalog of H. schachtii genes. Implementing a bioinformatic workflow, we identified 50 sequences coding for candidate secreted proteins. All of these contain a putative signal peptide required for entry into the secretory pathway and lack any transmembrane domain. Included are previously postulated cell-wall-degrading enzymes and other parasitism-related genes. Moreover, we provide the first report of an arabinogalactan endo-1,4-beta-galactosidase enzyme (EC 3.2.1.89) in animals. As sequence data increase at a rapid rate, developing high-throughput genomic screening is a necessity. The in silico approach described here is an effective way to identify putative secreted proteins and prioritize candidates for further studies.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2014
DOI: 10.1038/NG.2875
Publisher: MDPI AG
Date: 06-01-2023
DOI: 10.3390/PATHOGENS12010095
Abstract: The dynamic host-parasite mechanisms underlying hookworm infection establishment and maintenance in mammalian hosts remain poorly understood but are primarily mediated by hookworm’s excretory/secretory products (ESPs), which have a wide spectrum of biological functions. We used ultra-high performance mass spectrometry to comprehensively profile and compare female and male ESPs from the zoonotic human hookworm Ancylostoma ceylanicum, which is a natural parasite of dogs, cats, and humans. We improved the genome annotation, decreasing the number of protein-coding genes by 49% while improving completeness from 92 to 96%. Compared to the previous genome annotation, we detected 11% and 10% more spectra in female and male ESPs, respectively, using this improved version, identifying a total of 795 ESPs (70% in both sexes, with the remaining sex-specific). Using functional databases (KEGG, GO and Interpro), common and sex-specific enriched functions were identified. Comparisons with the exclusively human-infective hookworm Necator americanus identified species-specific and conserved ESPs. This is the first study identifying ESPs from female and male A. ceylanicum. The findings provide a deeper understanding of hookworm protein functions that assure long-term host survival and facilitate future engineering of transgenic hookworms and analysis of regulatory elements mediating the high-level expression of ESPs. Furthermore, the findings expand the list of potential vaccine and diagnostic targets and identify biologics that can be explored for anti-inflammatory potential.
Location: United States of America
Location: United States of America
No related grants have been discovered for Makedonka Mitreva.