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At least 19 recordsLinked to original sources
PubMed2026

Systematic discovery of pathogen effector functions across human pathogens and pathways.

Pathogens deploy effector proteins to exploit host cell biology, and most effector open reading frames (ORFs) are rapidly evolving and lack functional annotation. We developed the effector ORFeome (eORFeome), a scalable functional genomics platform encompassing 3,835 effector ORFs from diverse viruses, bacteria, and parasites. High-throughput barcoded screens across nuclear factor κB (NF-κB), apoptosis, p53, cGAS-STING, and major histocompatibility complex class I (MHC class I) pathways revealed novel pathway-modulating functions for hundreds of uncharacterized eORFs, unexpected activities of known effectors, and distinct pathway-specific functions encoded by single ORFs. Illustrating the power of this approach, we identified HHV6A U14 as a p53 antagonist, HHV7 U21 as a dual-function STING antagonist and MHC-I antigen display inhibitor, and adenoviral 13.6K/i-leader protein as a de novo-evolved TAP inhibitor that suppresses MHC-I display. These results establish a general framework for systematic effector annotation, uncover new mechanisms of host-pathogen interaction across kingdoms, and highlight pathogen effectors as a versatile toolkit for rewiring and probing human cellular pathways.

Humans↗
PubMed2025

In silico prediction method for plant Nucleotide-binding leucine-rich repeat- and pathogen effector interactions.

Plant Nucleotide-binding leucine-rich repeat (NLR) proteins play a crucial role in effector recognition and activation of Effector triggered immunity following pathogen infection. Genome sequencing advancements have led to the identification of a myriad of NLRs in numerous agriculturally important plant species. However, deciphering which NLRs recognize specific pathogen effectors remains challenging. Predicting NLR-effector interactions in silico will provide a more targeted approach for experimental validation, critical for elucidating function, and advancing our understanding of NLR-triggered immunity. In this study, NLR-effector protein complex structures were predicted using AlphaFold2-Multimer for all experimentally validated NLR-effector interactions reported in literature. Binding affinities- and energies were predicted using 97 machine learning models from Area-Affinity. We show that AlphaFold2-Multimer predicted structures have acceptable accuracy and can be used to investigate NLR-effector interactions in silico. Binding affinities for 58 NLR-effector complexes ranged between -8.5 and -10.6 log(K), and binding energies between -11.8 and -14.4 kcal/mol-1, depending on the Area-Affinity model used. For 2427 "forced" NLR-effector complexes, these estimates showed larger variability, enabling identification of novel NLR-effector interactions with 99% accuracy using an Ensemble machine learning model. The narrow range of binding energies- and affinities for "true" interactions suggest a specific change in Gibbs free energy, and thus conformational change, is required for NLR activation. This is the first study to provide a method for predicting NLR-effector interactions, applicable to all pathosystems. Finally, the NLR-Effector Interaction Classification (NEIC) resource can streamline research efforts by identifying NLRs important for plant-pathogen resistance, advancing our understanding of plant immunity.

Plant Proteins↗
PubMed2025

Diversification, loss, and virulence gains of the major effector AvrStb6 during continental spread of the wheat pathogen Zymoseptoria tritici.

Interactions between plant pathogens and their hosts are highly dynamic and mainly driven by pathogen effectors and plant receptors. Host-pathogen co-evolution can cause rapid diversification or loss of pathogen genes encoding host-exposed proteins. The molecular mechanisms that underpin such sequence dynamics remains poorly investigated at the scale of entire pathogen species. Here, we focus on AvrStb6, a major effector of the global wheat pathogen Zymoseptoria tritici, evolving in response to the cognate receptor Stb6, a resistance widely deployed in wheat. We comprehensively captured effector gene evolution by analyzing a global thousand-genome panel using reference-free sequence analyses. We found that AvrStb6 has diversified into 59 protein isoforms with a strong association to the pathogen spreading to new continents. Across Europe, we found the strongest differentiation of the effector consistent with high rates of Stb6 deployment. The AvrStb6 locus showed also a remarkable diversification in transposable element content with specific expansion patterns across the globe. We detected AvrStb6 gene losses and evidence for transposable element-mediated disruptions. We used virulence datasets of genome-wide association mapping studies to predict virulence changes across the global panel. Genomic predictions suggested marked increases in virulence on Stb6 cultivars concomitant with the spread of the pathogen to Europe and the subsequent spread to further continents. Finally, we genotyped French bread wheat cultivars for Stb6 and monitored resistant cultivar deployment concomitant with AvrStb6 evolution. Taken together, our data provides a comprehensive view of how a rapidly diversifying effector locus can undergo large-scale sequence changes concomitant with gains in virulence on resistant cultivars. The analyses highlight also the need for large-scale pathogen sequencing panels to assess the durability of resistance genes and improve the sustainability of deployment strategies.

Ascomycota↗
PubMed2025

Immune Aging in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a life-long autoimmune disease caused by the confluence of genetic and environmental variables that lead to loss of self-tolerance and persistent joint inflammation. RA occurs at the highest incidence in individuals >65 years old, implicating the aging process in disease susceptibility. Transformative approaches in molecular immunology and in functional genomics have paved the way for pathway paradigms underlying the replacement of immune homeostasis with autodestructive immunity in affected patients, including the process of immune aging. Patients with RA have a signature of premature immune aging, best understood for CD4+ T cells, which function as pathogenic effectors in this HLA class II-associated disease. Premature immune aging is present in healthy HLA-DRB1*04+ individuals, placing accelerated immune aging before joint inflammation. Aging-related molecular abnormalities directly implicated in turning RA CD4+ T cells into proinflammatory effector cells are linked to malfunction of subcellular organelles, such as mitochondria, lysosomes, lipid droplets, and the endoplasmic reticulum. Resulting changes in T cell behavior include cellular hypermobility, tissue invasiveness, unopposed mammalian target of rapamycin complex (mTORC)1 activation, excessive release of tumor necrosis factor, lysosomal failure, clonal expansion, and immunogenic cell death. Aged and metabolically reprogrammed T cells in patients with RA are accompanied by age-associated B cells, which specialize in autoantibody production. Clonal hematopoiesis drives myeloid cell aging by producing aged monocytes and hypermetabolic macrophages, which sustain the process of inflammaging. Here, we synthesize insights into the relationship of RA risk and immune aging and discuss mechanisms through which immune aging can cause autoimmunity.

Humans↗
PubMed2025

Annotation of RxLR Effectors in Oomycete Genomes.

Pathogens have evolved effector proteins to suppress host immunity and facilitate plant infections. RxLR effectors are small, secreted effector proteins with conserved RxLR and dEER amino acid motifs at the N terminus and highly variable C termini and are commonly found in oomycete species. We provide computational approaches to annotate RxLR candidate effector genes in a genome assembly in FASTA format with an available GFF file. Hidden Markov Modeling (HHM) is used in combination with regular expressions to search for RxLR and EER amino acid patterns.

Oomycetes↗
PubMed2025

Exploring effector protein dynamics and natural fungicidal potential in rice blast pathogen Magnaporthe oryzae.

Rice blast, caused by Magnaporthe oryzae, is one of the most destructive fungal diseases in rice, resulting in major economic losses worldwide. Genetic and genomic studies have identified key genes and proteins, such as AvrPik variants and MAX proteins, that are crucial for the pathogen's virulence. These effector proteins interact with specific alleles of the Pik gene family on rice chromosome 11, modulating the host's immune response. In this study, we investigated 35 plant-derived metabolites known for their antifungal properties as potential fungicides against M. oryzae. Using molecular docking, we identified Hecogenin and Cucurbitacin E as strong binders to MAX40 and APIKL2A proteins, which are essential for the fungus's immune evasion and pathogenicity. Molecular dynamics simulations further confirmed that these compounds form stable, strong interactions with the target proteins, validating their potential as therapeutic agents. Additionally, the compounds were evaluated based on Lipinski's rule of five and toxicity predictions, indicating their suitability for agricultural use. These results suggest that Hecogenin and Cucurbitacin E could serve as promising lead candidates in the development of novel fungicides for rice blast, offering new strategies for crop protection and sustainable agricultural practices.

Oryza↗
PubMed2026

Trade-Offs Associated with Virulence of Soybean Cyst Nematode on the Broad-Spectrum Resistance Source PI 437654.

The soybean cyst nematode (SCN; Heterodera glycines) poses a major challenge to soybean production, intensified by the declining effectiveness of natural resistance against this pathogen. Although the use of resistant soybean varieties can be effective, their widespread and repeated use ultimately results in the emergence of virulent nematode populations that can successfully attack these resistant hosts. To assess for potential trade-offs between virulence and fitness, we investigated the hatch response, penetration rate, and reproductive potential of SCN adapted to overcome the broad-spectrum resistance source PI 437654. The hatching process is a critical phase in the life cycle of the SCN, influencing its ability to infect hosts and complete its life cycle. Our results indicated that SCN populations exhibit preferential and heightened hatch responses to their adapted host compared to alternative hosts, regardless of their virulence profile. Additionally, we found that SCN populations adapted to overcome broad-spectrum resistance showed reduced reproductive success on susceptible hosts compared to unadapted populations. This reduction in reproductive success was not attributed to differences in hatch response or penetration rates. The results from our study highlight the potential trade-offs associated with SCN virulence adaptation and emphasize the importance of considering these evolutionary dynamics in developing sustainable management strategies.

Disease Control and Pest Management↗
PubMed2026

Systematic Identification and Functional Characterisation of Colletotrichum fructicola Effectors During Camellia oleifera Colonisation.

Camellia oleifera is an important woody oil crop in southern China, but its production is severely threatened by anthracnose caused by Colletotrichum fructicola. C. fructicola deploys secreted effector proteins to establish infection. However, systematic identification and functional characterisation of C. fructicola effector genes upregulated during infection remains largely unexplored. Here, we integrated genome-wide secretome prediction with RNA-seq data from C. oleifera leaves inoculated with C. fructicola to identify candidate effectors induced during infection, followed by functional screening, targeted gene deletion, complementation and pathogenicity assays. Five novel effectors required for C. fructicola full virulence were identified, all of which suppressed Bax-induced cell death in Nicotiana benthamiana. Targeted deletion of the corresponding genes in C. fructicola reduced lesion areas by 47%-78% on C. oleifera leaves and by up to 67% on apple fruits, whereas complementation restored their virulence to wild-type levels. Transcriptomic profiling of infected postharvest C. oleifera fruits identified differentially expressed genes enriched in GO terms related to copper ion response, as well as in KEGG pathways associated with phenylpropanoid biosynthesis, taurine and hypotaurine metabolism, and plant-pathogen interactions. In addition, superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) activities, as well as malondialdehyde content, were altered in C. oleifera leaves inoculated with the effector-deletion mutants compared with those infected with the wild-type strain, suggesting that these effectors may contribute to the modulation of host oxidative stress responses. Taken together, our findings provide genetic and physiological evidence that these effectors contribute to C. fructicola virulence, offering potential targets for anthracnose control.

Colletotrichum↗
PubMed2026

Conserved protein folds underpin the diversification of secreted proteins in a fungal pathogen.

BACKGROUND: During host colonization, fungal plant pathogens secrete effector-like proteins that alter host cell physiology and target plant-associated microbes. However, rapid evolution and low sequence conservation hinder the study and characterization of these proteins. The fungus Zymoseptoria passerinii infects Hordeum spp. and includes lineages adapted to wild and domesticated barley. To date, the evolution of effector-like proteins in this species has not been addressed. RESULTS: We combined multiple structure-based and network analyses to unravel the secretome of Z. passerinii. We first compared AlphaFold2 and ESMFold predictions to establish the baseline for structural analyses. We identified 72 structural clusters in the secretome, revealing fold-level relationships across divergent sequences. We showed that effector-like proteins with predicted host immune-interfering functions evolved from a limited group of protein folds, whereas proteins with predicted antimicrobial properties were distributed across fold groups. Physicochemical comparisons indicate that putative antimicrobial effectors predominantly emerged through amino acid replacements on common effector-enriched scaffolds in Z. passerinii, reconfiguring surface charge and electrostatics. We analyzed intra- and interspecific variation in selected effector-enriched families by comparing Z. passerinii proteins and homologs across the genus Zymoseptoria. We describe constrained core folds, with local variation in loop and surface-exposed regions, consistent with fold stability while still enabling protein diversification. We further report that putative antimicrobial effector homologs are broadly distributed across the genus despite sequence divergence. CONCLUSIONS: The secretome of Z. passerinii is organized around common structural folds that support diverse biological roles, including host manipulation and host-associated microbial interactions. Conserved scaffolds combined with surface and physicochemical variation likely contribute to rapid adaptive evolution of effector-like proteins in Z. passerinii.

Fungal Proteins↗
PubMed2025

Diversification of an emerging bacterial plant pathogen; insights into the global spread of Xanthomonas euvesicatoria pv. perforans.

Emerging and re-emerging plant diseases continue to present multifarious threats to global food security. Considerable recent efforts are therefore being channeled towards understanding the nature of pathogen emergence, their spread and evolution. Xanthomonas euvesicatoria pv. perforans (Xep), one of the causal agents of bacterial spot of tomato, rapidly emerged and displaced other bacterial spot xanthomonads in many tomato production regions around the world. In less than three decades, it has become a dominant xanthomonad pathogen in tomato production systems across the world and presents a compelling example for understanding diversification of recently emerged bacterial plant pathogens. Although Xep has been continuously monitored in Florida since its discovery, the global population structure and evolution at the genome-scale is yet to be fully explored. The objectives of this work were to determine genetic diversity globally to ascertain if different tomato production regions contain genetically distinct Xep populations, to examine genetic relatedness of strains collected in tomato seed production areas in East Asia and other production regions, and to evaluate variation in type III secretion effectors, which are critical pathogenicity and virulence factors, in relationship to population structure. We used genome data from 270 strains from 13 countries for phylogenetic analysis and characterization of type III effector gene diversity among strains. Our results showed notable genetic diversity in the pathogen. We found genetically similar strains in distant tomato production regions, including seed production regions, and diversification over the past 100 years, which is consistent with intercontinental dissemination of the pathogen in hybrid tomato production chains. Evolution of the Xep pangenome, including the acquisition and loss of type III secreted effectors, is apparent within and among phylogenetic lineages. The apparent long-distance movement of the pathogen, together with variants that may not yet be widely distributed, poses risks of emergence of new variants in tomato production.

Xanthomonas↗
PubMed2023

Evolution and assembly of Anopheles aquasalis's immune genes: primary malaria vector of coastal Central and South America and the Caribbean Islands.

Anophelines are vectors of malaria, the deadliest disease worldwide transmitted by mosquitoes. The availability of genomic data from various Anopheles species allowed evolutionary comparisons of the immune response genes in search of alternative vector control of the malarial parasites. Now, with the Anopheles aquasalis genome, it was possible to obtain more information about the evolution of the immune response genes. Anopheles aquasalis has 278 immune genes in 24 families or groups. Comparatively, the American anophelines possess fewer genes than Anopheles gambiae s. s., the most dangerous African vector. The most remarkable differences were found in the pathogen recognition and modulation families like FREPs, CLIP and C-type lectins. Even so, genes related to the modulation of the expression of effectors in response to pathogens and gene families that control the production of reactive oxygen species were more conserved. Overall, the results show a variable pattern of evolution in the immune response genes in the anopheline species. Environmental factors, such as exposure to different pathogens and differences in the microbiota composition, could shape the expression of this group of genes. The results presented here will contribute to a better knowledge of the Neotropical vector and open opportunities for malaria control in the endemic-affected areas of the New World.

Animals↗
PubMed2025

Transposable elements create distinct genomic niches for effector evolution among Magnaporthe oryzae lineages.

BACKGROUND: Plant-pathogen interactions are characterized by evolutionary arms races. At the molecular level, fungal effectors can target important plant functions, while plants evolve to improve effector recognition. Rapid evolution in genes encoding effectors can be facilitated by transposable elements (TEs). In Magnaporthe oryzae, the causal agent of blast disease in several cereals and grasses, TEs play important roles in chromosomal evolution as well as the gain or loss of effector genes in host specialized lineages. However, a global understanding of TE dynamics driving effector evolution at population scale and across lineages is lacking. RESULTS: Here, we focus on 16 AVR effector loci assessed across a global sampling of 11 reference genomes and 447 newly generated draft genome assemblies from publicly available short-read sequencing data across all major M. oryzae lineages and outgroups. We classified each effector based on evidence for duplication, deletion and translocation processes among lineages. Next, we determined AVR gain and loss dynamics across lineages allowing for a broad categorization of effector dynamics. Each AVR was integrated in a distinct genomic niche determined by the TE activity profile contributing to the diversification at the locus. We quantified TE contributions to effector niches and found that TE identity helped diversify AVR loci. We used the large genomic dataset to recapitulate the evolution of the rice blast AVR1-CO39 locus. CONCLUSIONS: Taken together, our work demonstrates how TE dynamics are an integral component of M. oryzae effector evolution, likely facilitating escape from host recognition. In-depth tracking of effector loci is a valuable tool to predict the durability of host resistance.

Ascomycota↗
PubMed2024

A gene with a thousand alleles: The hyper-variable effectors of plant-parasitic nematodes.

Pathogens are engaged in a fierce evolutionary arms race with their host. The genes at the forefront of the engagement between kingdoms are often part of diverse and highly mutable gene families. Even in this context, we discovered unprecedented variation in the hyper-variable (HYP) effectors of plant-parasitic nematodes. HYP effectors are single-gene loci that potentially harbor thousands of alleles. Alleles vary in the organization, as well as the number, of motifs within a central hyper-variable domain (HVD). We dramatically expand the HYP repertoire of two plant-parasitic nematodes and define distinct species-specific "rules" underlying the apparently flawless genetic rearrangements. Finally, by analyzing the HYPs in 68 individual nematodes, we unexpectedly found that despite the huge number of alleles, most individuals are germline homozygous. These data support a mechanism of programmed genetic variation, termed HVD editing, where alterations are locus specific, strictly governed by rules, and theoretically produce thousands of variants without errors.

Animals↗
PubMed2026

Integrated analysis of ATAC-seq and RNA-seq reveals the TCP-ARF molecular module related to pathogenic process of phytoplasma infection in Paulownia fortunei.

BACKGROUND: Witches’ broom is an important disease of the Paulownia fortunei. Understanding the pathogenesis of witches’ broom is a prerequisite for its prevention and control. Phytoplasma is the pathogen of Paulownia witches’ broom. RESULTS: We investigated the changes in chromatin accessibility before and after phytoplasma infection in Paulownia fortunei by analyzing the DNA accessibility (ATAC-seq). In phytoplasma-infected P. fortunei (PFI) compared to healthy samples (PF), the closed regions of chromatin(1187 regions) were three times more than the open regions (352 regions). Fifty one percent of the accessible chromatin regions were overlapped with either H3K27ac or H3K9ac peaks. The closed regions were enriched in the conserved motif TGGGC[CT] that is recognized by the TCP transcription factor family. The closed regions in PFI are intersected with ARF family gene locus. The gene PfARF3 was verified to interact with the PfTCP23 transcription factor. The PfTCP23 was predicted to be interacted with the effector pawb44 in the pathogen of phytoplasma. CONCLUSIONS: The phytoplasma infection in P. fortunei is involved in the chromatin changes of the DNA accessibility and histone modification. The binding regions of TCP23 were found to be changed mostly in the accessibility between PFI and PF. The TCP-ARF module was found to be the possible regulatory module inducing the crinkled leaf trait.

RNA-Seq↗
PubMed2026

Spore type-specific gene expression profiles underlying development and leaf infection processes of Colletotrichum graminicola.

Colletotrichum graminicola causes significant losses of the staple crop maize worldwide. The fungus produces two distinct asexual spore types, oval and falcate conidia, which show unique processes in development and plant interaction. Based on genome resequencing of our laboratory strain (CgM2/M1.001), we investigated the gene expression profiles of oval and falcate conidia during development and early leaf infection using RNA-seq. Our results reveal specific gene expression profiles between the two spore types, indicating fundamental differences in their developmental programs that reflect different modes of infection. We identified expression patterns discriminating both conidia types from mycelium and spore type-specific ones for genes encoding transcription factors, conserved fungal developmental genes, transporters, genes of secondary metabolite clusters, and pathogenicity-related functions, including effectors and carbohydrate-active enzymes (CAZymes). Our study shows that despite the identical genomic basis, oval and falcate conidia show unique transcriptomes across vegetative development and early plant interaction. Taking together, these results provide new insights into the molecular mechanisms determining the biology of C. graminicola and its interaction with the plant host.

Colletotrichum graminicola↗
PubMed2025

Expansion of secreted cystine knot proteins reveals virulence factors in the human fungal pathogen Histoplasma.

Identifying fungal secreted factors that influence host infection remains a key challenge in microbial pathogenesis. While secreted effectors, particularly small cysteine-rich proteins, are well characterized in plant fungal pathogens, their counterparts in mammalian pathogens are understudied. We apply criteria from plant fungal effectors to the mammalian fungal pathogen Histoplasma, yielding a set of putative effectors highly enriched for knottins, proteins that adopt a distinctive cystine knot fold. Using an algorithm, we further identify 25 putative knottins in the Histoplasma genome, revealing a significant expansion of knottin genes. Knottin domains are found in diverse molecules but play an unknown role in virulence. Functional studies of individual Histoplasma knottins demonstrate their critical roles in intracellular survival and host cell lysis during macrophage infection as well as virulence in vivo. These findings highlight the importance of knottins in fungal pathogenesis and suggest their broader relevance for discovering conserved mechanisms of host manipulation.

Histoplasma↗
PubMed2026

TALEs, TALENs, and TALE Base Editors: From Plant Pathology to Biotechnology.

TALEs (transcription activator-like effectors) are an excellent example of how studying pathogen-host interactions can lead to significant biotechnology inventions. TALEs are bacterial effectors that are translocated into plant cells via a bacterial type III secretion system. Once inside the host cell, they are imported into the nucleus to bind specific promoters and induce expression of target genes, thereby supporting the bacterial infection. TALEs are found throughout many, but not all, Xanthomonas pathovars, which can be severe pathogens of different crops. The key feature of TALEs is their modular DNA-binding domain, which allows a simple evolutionary adaptation to novel DNA sequences as well as simple cloning of designer TALEs with desired DNA-binding specificity. Accordingly, TALE nucleases started the genome-editing revolution, and TALE base editors are the latest tools to efficiently edit chloroplast and mitochondrial genomes. We review recent advances in Xanthomonas genomics, synthesize current knowledge about naturally occurring TALEs, and highlight current roles of TALEs in genome editing and synthetic biology.

Xanthomonas↗