Dengue Virus Non-Structural Protein 5 as a Versatile, Multi-Functional Effector in Host-Pathogen Interactions.
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ABSTRACT:
SUBMITTER: Bhatnagar P
PROVIDER: S-EPMC8015806 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Data Access Committee EGAC00001003063
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Project description:The success of plant-pathogenic fungi mostly relies on their arsenal of virulence factors which are expressed and delivered into the host tissue during colonization. The biotrophic fungal pathogen Ustilago hordei causes covered smut disease on both barley and oat. In this study, we combined cytological, genomics and molecular biological methods to achieve a better understanding of the molecular interactions in the U. hordei-barley pathosystem. Microscopic analysis revealed that U. hordei densely colonizes barley leaves on penetration, in particular the vascular system. Transcriptome analysis of U. hordei at different stages of host infection revealed differential expression of the transcript levels of 273 effector gene candidates. Furthermore, U. hordei transcriptionally activates core effector genes which may suppress even non-host early defence responses. Based on expression profiles and novelty of sequences, knockout studies of 14 effector candidates were performed in U. hordei, which resulted in the identification of four virulence factors required for host colonization. Yeast two-hybrid screening identified potential barley targets for two of the effectors. Overall, this study provides a first systematic analysis of the effector repertoire of U. hordei and identifies four effectors (Uvi1-Uvi4) as virulence factors for the infection of barley.
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Project description:Forests are under threat from pests, pathogens, and changing climate. A major forest pathogen worldwide is the hemibiotroph Dothistroma septosporum, which causes dothistroma needle blight (DNB) of pines. While D. septosporum uses effector proteins to facilitate host infection, it is currently unclear whether any of these effectors are recognised by immune receptors to activate the host immune system. Such information is needed to identify and select disease resistance against D. septosporum in pines. We predicted and investigated apoplastic D. septosporum candidate effectors (DsCEs) using bioinformatics and plant-based experiments. We discovered DsCEs that trigger cell death in the angiosperm Nicotiana spp., indicative of a hypersensitive defence response and suggesting their recognition by immune receptors in non-host plants. In a first for foliar forest pathogens, we developed a novel protein infiltration method to show that tissue-cultured pine shoots can respond with a cell death response to a DsCE, as well as to a reference cell death-inducing protein. The conservation of responses across plant taxa suggests that knowledge of pathogen-angiosperm interactions may also be relevant to pathogen-gymnosperm interactions. These results contribute to our understanding of forest pathogens and may ultimately provide clues to disease immunity in both commercial and natural forests.
| S-EPMC8497623 | biostudies-literature
Project description:Since 2005, the Pathogen-Host Interactions Database (PHI-base) has manually curated experimentally verified pathogenicity, virulence and effector genes from fungal, bacterial and protist pathogens, which infect animal, plant, fish, insect and/or fungal hosts. PHI-base (www.phi-base.org) is devoted to the identification and presentation of phenotype information on pathogenicity and effector genes and their host interactions. Specific gene alterations that did not alter the in host interaction phenotype are also presented. PHI-base is invaluable for comparative analyses and for the discovery of candidate targets in medically and agronomically important species for intervention. Version 4.12 (September 2021) contains 4387 references, and provides information on 8411 genes from 279 pathogens, tested on 228 hosts in 18, 190 interactions. This provides a 24% increase in gene content since Version 4.8 (September 2019). Bacterial and fungal pathogens represent the majority of the interaction data, with a 54:46 split of entries, whilst protists, protozoa, nematodes and insects represent 3.6% of entries. Host species consist of approximately 54% plants and 46% others of medical, veterinary and/or environmental importance. PHI-base data is disseminated to UniProtKB, FungiDB and Ensembl Genomes. PHI-base will migrate to a new gene-centric version (version 5.0) in early 2022. This major development is briefly described.
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Project description:Damage to our genomes triggers cellular senescence characterised by stable cell cycle arrest and a pro-inflammatory secretome that prevents the unrestricted growth of cells with pathological potential. In this way, senescence can be considered a powerful innate defence against cancer and viral infection. However, damage accumulated during ageing increases the number of senescent cells and this contributes to the chronic inflammation and deregulation of the immune function, which increases susceptibility to infectious disease in ageing organisms. Bacterial and viral pathogens are masters of exploiting weak points to establish infection and cause devastating diseases. This review considers the emerging importance of senescence in the host-pathogen interaction: we discuss the pathogen exploitation of ageing cells and senescence as a novel hijack target of bacterial pathogens that deploys senescence-inducing toxins to promote infection. The persistent induction of senescence by pathogens, mediated directly through virulence determinants or indirectly through inflammation and chronic infection, also contributes to age-related pathologies such as cancer. This review highlights the dichotomous role of senescence in infection: an innate defence that is exploited by pathogens to cause disease.
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Project description:The goal of this project is to understand the etiology and pathology of host-pathogen interaction using high-throughput cellular phenotyping. By combining the expertise in pathogen biology, informatics and stem cell biology across the institute, this project will use targeted genetic modification in mouse embryonic stem cells to identify functions of host genes in innate immunity. We will also explore the biology of mouse embryonic stem cells and their differentiation into immune competent cells. To this end we will generate homozygous and inducible knockout lines in mouse embryonic stem cells, which will be differentiated into immune competent cells, such as macrophages or dendritic cells. These will be subjected to a panel of immune challenge and stimulation assays to characterise the functions of the disrupted genes. To identify new functions for mammalian genes in innate immunity we will:\Generate a panel of homozygous inducible gene knockout mouse ES cell lines working from a list of ca. 80 candidate genes (MGP phenotyping and GWAS hits). \Scale up differentiation protocols for immune challenge and stimulation assays.\Benchmark in vitro differentiated ES cell models against primary immune cells from selected MGP mouse lines and eventually against human iPS cells.\Screen a panel of 30 genetically modified cell lines in immunological challenge and stimulation assays, defining phenotypes at the cellular level by high content imaging, biochemically by assaying cytokine production, and at the molecular level by transcriptome analysis.\Define novel gene functions in innate immunity through network analysis of gene expression data from all challenged cell lines.\In the longer term scale up the production and phenotyping of genetically modified cell lines (mouse or human as appropriate).This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
2014-03-25 | E-ERAD-234 | biostudies-arrayexpress
Project description:Serpins are a broadly distributed superfamily of protease inhibitors that are present in all kingdoms of life. The acronym, serpin, is derived from their function as potent serine proteases inhibitors. Early studies of serpins focused on their functions in haemostasis since modulating serine proteases activities are essential for coagulation. Additional research has revealed that serpins function in infection and inflammation, by modulating serine and cysteine proteases activities. The aim of this review is to summarize the accumulating findings and current understanding of the functions of serpins in host-pathogen interactions, serving as host defense proteins as well as pathogenic factors. We also discuss the potential crosstalk between host and pathogen serpins. We anticipate that future research will elucidate the therapeutic value of this novel target.
| S-EPMC5889911 | biostudies-literature
Project description:BackgroundUnderstanding the mechanisms that control rates of disease progression in humans and other species is an important area of research relevant to epidemiology and to translating studies in small laboratory animals to humans. Body size and metabolic rate influence a great number of biological rates and times. We hypothesize that body size and metabolic rate affect rates of pathogenesis, specifically the times between infection and first symptoms or death.Methods and principal findingsWe conducted a literature search to find estimates of the time from infection to first symptoms (t(S)) and to death (t(D)) for five pathogens infecting a variety of bird and mammal hosts. A broad sampling of diseases (1 bacterial, 1 prion, 3 viruses) indicates that pathogenesis is controlled by the scaling of host metabolism. We find that the time for symptoms to appear is a constant fraction of time to death in all but one disease. Our findings also predict that many population-level attributes of disease dynamics are likely to be expressed as dimensionless quantities that are independent of host body size.Conclusions and significanceOur results show that much variability in host pathogenesis can be described by simple power functions consistent with the scaling of host metabolic rate. Assessing how disease progression is controlled by geometric relationships will be important for future research. To our knowledge this is the first study to report the allometric scaling of host/pathogen interactions.
| S-EPMC2042517 | biostudies-literature
Project description:Uropathogenic E. coli (UPEC), which cause urinary tract infections (UTI), utilize type 1 pili, a chaperone usher pathway (CUP) pilus, to cause UTI and colonize the gut. The pilus rod, comprised of repeating FimA subunits, provides a structural scaffold for displaying the tip adhesin, FimH. We solved the 4.2 Å resolution structure of the type 1 pilus rod using cryo-electron microscopy. Residues forming the interactive surfaces that determine the mechanical properties of the rod were maintained by selection based on a global alignment of fimA sequences. We identified mutations that did not alter pilus production in vitro but reduced the force required to unwind the rod. UPEC expressing these mutant pili were significantly attenuated in bladder infection and intestinal colonization in mice. This study elucidates an unappreciated functional role for the molecular spring-like property of type 1 pilus rods in host-pathogen interactions and carries important implications for other pilus-mediated diseases.
| S-EPMC5798934 | biostudies-literature
Project description:The success of plant pathogenic fungi mostly relies on their arsenal of virulence factors that are expressed and delivered into the host tissue during colonization. The biotrophic fungal pathogen Ustilago hordei causes covered smut disease on both barley and oat. The biotrophic interaction of the fungus with its host plant starts with formation of appressorium and subsequent penetration of invasive hyphae into the plant cell, in which the plasma membrane of the infected cell gets invaginated and encases the penetrating hypha. After penetration, the fungus grows towards and in later stages along the vascular bundles, which contain assimilates and metabolites, representing a source of nutrients for the fungus. In this study, we combined cytological, genomics and molecular biological methods to achieve a better understanding of the molecular interactions in the U. hordei-barley pathosystem. This study focuses on the genome-wide Agilent Microarray-based transcriptome analysis of U. hordei during early stages (20 hpi, 40 hpi, 3 dpi, 6 dpi) of the biotrophic interaction in comparison to axenic culture growth. This should give insights into the molecular processes during these stages by the identification of regulated genes. Furthermore, the regulation of putative secreted enzymes and effector proteins can be studied. Transcriptome analysis of U. hordei at different stages of host infection revealed 273 effector gene candidates with differentially expressed transcript levels. Furthermore, U. hordei transcriptionally activates core-effector genes that may suppress even non-host early defense responses. It could be shown that about one half of the U. hordei open reading frames are differentially regulated during at least one of the analyzed stages. Based on the transcriptome data, some of them were identified to be involved in stage-specific processes, e.g. in the nutrient acquisition by the induction of carbohydrate transporters during the later stages of infection. Furthermore, a set of strongly induced genes was identified, which encode for secreted proteins. The acquired datasets show a strong induction of stage-specific secreted effector proteins, whose functions remain unclear. Based on the expression values, a group of 16 promising candidates was chosen for functional characterization. The success of plant pathogenic fungi mostly relies on their arsenal of virulence factors that are expressed and delivered into the host tissue during colonization. The biotrophic fungal pathogen Ustilago hordei causes covered smut disease on both barley and oat. The biotrophic interaction of the fungus with its host plant starts with formation of appressorium and subsequent penetration of invasive hyphae into the plant cell, in which the plasma membrane of the infected cell gets invaginated and encases the penetrating hypha. After penetration, the fungus grows towards and in later stages along the vascular bundles, which contain assimilates and metabolites, representing a source of nutrients for the fungus. In this study, we combined cytological, genomics and molecular biological methods to achieve a better understanding of the molecular interactions in the U. hordei-barley pathosystem. This study focuses on the genome-wide Agilent Microarray-based transcriptome analysis of U. hordei during early stages (20 hpi, 40 hpi, 3 dpi, 6 dpi) of the biotrophic interaction in comparison to axenic culture growth. This should give insights into the molecular processes during these stages by the identification of regulated genes. Furthermore, the regulation of putative secreted enzymes and effector proteins can be studied. Transcriptome analysis of U. hordei at different stages of host infection revealed 273 effector gene candidates with differentially expressed transcript levels. Furthermore, U. hordei transcriptionally activates core-effector genes that may suppress even non-host early defense responses. It could be shown that about one half of the U. hordei open reading frames are differentially regulated during at least one of the analyzed stages. Based on the transcriptome data, some of them were identified to be involved in stage-specific processes, e.g. in the nutrient acquisition by the induction of carbohydrate transporters during the later stages of infection. Furthermore, a set of strongly induced genes was identified, which encode for secreted proteins.The acquired datasets show a strong induction of stage-specific secreted effector proteins, whose functions remain unclear. Based on the expression values, a group of 16 promising candidates was chosen for functional characterization.
2018-07-19 | GSE117325 | GEO