IF 6.4 1区生物学

eLife Pub Date : 2025-05-28 DOI: 10.7554/eLife.102301

Elizabeth J Fay, Kolya Isterabadi, Charles M Rezanka, Jessica Le, Matthew D Daugherty

{"title":"Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates.","authors":"Elizabeth J Fay, Kolya Isterabadi, Charles M Rezanka, Jessica Le, Matthew D Daugherty","doi":"10.7554/eLife.102301","DOIUrl":"10.7554/eLife.102301","url":null,"abstract":"Receptor interacting protein kinases (RIPK) RIPK1 and RIPK3 play important roles in diverse innate immune pathways. Despite this, some RIPK1/3-associated proteins are absent in specific vertebrate lineages, suggesting that some RIPK1/3 functions are conserved, while others are more evolutionarily labile. Here, we perform comparative evolutionary analyses of RIPK1-5 and associated proteins in vertebrates to identify lineage-specific rapid evolution of RIPK3 and RIPK1 and recurrent loss of RIPK3-associated proteins. Despite this, diverse vertebrate RIPK3 proteins are able to activate NF-κB and cell death in human cells. Additional analyses revealed a striking conservation of the RIP homotypic interaction motif (RHIM) in RIPK3, as well as other human RHIM-containing proteins. Interestingly, diversity in the RIPK3 RHIM can tune activation of NF-κB while retaining the ability to activate cell death. Altogether, these data suggest that NF-κB activation is a core, conserved function of RIPK3, and the RHIM can tailor RIPK3 function to specific needs within and between species.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An antisense oligonucleotide-based strategy to ameliorate cognitive dysfunction in the 22q11.2 Deletion Syndrome. 基于反义寡核苷酸的策略改善22q11.2缺失综合征的认知功能障碍。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-27 DOI: 10.7554/eLife.103328

Pratibha Thakur, Martin Lackinger, Anastasia Diamantopoulou, Sneha Rao, Yijing Chen, Khakima Khalizova, Annie Ferng, Curt Mazur, Holly Kordasiewicz, Robert J Shprintzen, Sander Markx, Bin Xu, Joseph A Gogos

{"title":"An antisense oligonucleotide-based strategy to ameliorate cognitive dysfunction in the 22q11.2 Deletion Syndrome.","authors":"Pratibha Thakur, Martin Lackinger, Anastasia Diamantopoulou, Sneha Rao, Yijing Chen, Khakima Khalizova, Annie Ferng, Curt Mazur, Holly Kordasiewicz, Robert J Shprintzen, Sander Markx, Bin Xu, Joseph A Gogos","doi":"10.7554/eLife.103328","DOIUrl":"10.7554/eLife.103328","url":null,"abstract":"Adults and children with the 22q11.2 Deletion Syndrome demonstrate cognitive, social, and emotional impairments and high risk for schizophrenia. Work in mouse model of the 22q11.2 deletion provided compelling evidence for abnormal expression and processing of microRNAs. A major transcriptional effect of the microRNA dysregulation is upregulation of Emc10, a component of the ER membrane complex, which promotes membrane insertion of a subset of polytopic and tail-anchored membrane proteins. We previously uncovered a key contribution of EMC10 in mediating the behavioral phenotypes observed in 22q11.2 deletion mouse models. Here, we show that expression and processing of miRNAs is abnormal and EMC10 expression is elevated in neurons derived from 22q11.2 deletion carriers. Reduction of EMC10 levels restores defects in neurite outgrowth and calcium signaling in patient neurons. Furthermore, antisense oligonucleotide administration and normalization of Emc10 in the adult mouse brain not only alleviates cognitive deficits in social and spatial memory but remarkably sustains these improvements for over 2 months post-injection, indicating its therapeutic potential. Broadly, our study integrates findings from both animal models and human neurons to elucidate the translational potential of modulating EMC10 levels and downstream targets as a specific venue to ameliorate disease progression in 22q11.2 Deletion Syndrome.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evolutionary unique N-glycan-dependent protein quality control system plays pivotal roles in cellular fitness and extracellular vesicle transport in Cryptococcus neoformans. 进化独特的n-聚糖依赖蛋白质量控制系统在新型隐球菌的细胞适应性和细胞外囊泡运输中起关键作用。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-27 DOI: 10.7554/eLife.103729

Catia Mota, Kiseung Kim, Ye Ji Son, Eun Jung Thak, Su-Bin Lee, Ju-El Kim, Jeong-Kee Yoon, Min-Ho Kang, Heeyoun Hwang, Yong-Sun Bahn, J Andrew Alspaugh, Hyun Ah Kang

{"title":"Evolutionary unique N-glycan-dependent protein quality control system plays pivotal roles in cellular fitness and extracellular vesicle transport in Cryptococcus neoformans.","authors":"Catia Mota, Kiseung Kim, Ye Ji Son, Eun Jung Thak, Su-Bin Lee, Ju-El Kim, Jeong-Kee Yoon, Min-Ho Kang, Heeyoun Hwang, Yong-Sun Bahn, J Andrew Alspaugh, Hyun Ah Kang","doi":"10.7554/eLife.103729","DOIUrl":"10.7554/eLife.103729","url":null,"abstract":"A conserved N-glycan-dependent endoplasmic reticulum protein quality control (ERQC) system has evolved in eukaryotes to ensure accuracy during glycoprotein folding. The human pathogen Cryptococcus neoformans possesses a unique N-glycosylation pathway that affects microbial physiology and interactions with the infected host. To investigate the molecular features and functions of the ERQC system in C. neoformans, we characterized a set of mutants with deletion of genes coding for the ERQC sensor UDP-glucose:glycoprotein glucosyltransferase (UGG1) and putative α1,2-mannose-trimming enzymes (MNS1, MNS101, MNL1, and MNL2). The ugg1Δ, mns1Δ, mns101Δ, and mns1Δ101Δ mutants showed alterations in N-glycan profiles, defective cell surface organization, decreased survival in host cells, and varying degrees of reduced in vivo virulence. The ugg1Δ strain exhibited severely impaired extracellular secretion of capsular polysaccharides and virulence-related enzymes. Comparative transcriptome analysis showed the upregulation of protein folding, proteolysis, and cell wall remodeling genes, indicative of induced endoplasmic reticulum stress. However, no apparent changes were observed in the expression of genes involved in protein secretion or capsule biosynthesis. Additionally, extracellular vesicle (EV) analysis combined with proteomic analysis showed significant alterations in the number, size distribution, and cargo composition of EVs in ugg1Δ. These findings highlight the essential role of the functional ERQC system for cellular fitness under adverse conditions and proper EV-mediated transport of virulence factors, which are crucial for the full fungal pathogenicity of C. neoformans.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Scrutinized lipid utilization disrupts Amphotericin-B responsiveness in clinical isolates of Leishmania donovani. 仔细检查脂质利用破坏两性霉素b在临床分离利什曼多诺瓦原虫的反应。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-27 DOI: 10.7554/eLife.102857

Supratim Pradhan, Dhruba Dhar, Debolina Manna, Shubhangi Chakraborty, Arkapriya Bhattacharyya, Khushi Chauhan, Rimi Mukherjee, Abhik Sen, Krishna Pandey, Soumen Das, Budhaditya Mukherjee

{"title":"Scrutinized lipid utilization disrupts Amphotericin-B responsiveness in clinical isolates of Leishmania donovani.","authors":"Supratim Pradhan, Dhruba Dhar, Debolina Manna, Shubhangi Chakraborty, Arkapriya Bhattacharyya, Khushi Chauhan, Rimi Mukherjee, Abhik Sen, Krishna Pandey, Soumen Das, Budhaditya Mukherjee","doi":"10.7554/eLife.102857","DOIUrl":"10.7554/eLife.102857","url":null,"abstract":"The management of Leishmania donovani (LD), responsible for fatal visceral leishmaniasis (VL), faces increasing challenges due to rising drug unresponsiveness, leading to increasing treatment failures. While hypolipidemia characterizes VL, LD, a cholesterol auxotroph, relies on host lipid scavenging for its intracellular survival. The aggressive pathology, in terms of increased organ parasite load, observed in hosts infected with antimony-unresponsive-LD (LD-R) as compared to their sensitive counterparts (LD-S), highlights LD-R's heightened reliance on host lipids. Here, we report that LD-R-infection in mice promotes fluid-phase endocytosis in the host macrophages, selectively accumulating neutral lipids while excluding oxidized-low-density lipoprotein (LDL). LD-R enhances the fusion of endocytosed LDL-vesicles with its phagolysosomal membrane and inhibits cholesterol mobilization from these vesicles by suppressing NPC-1. This provides LD-R amastigotes with excess lipids, supporting their rapid proliferation and membrane synthesis. This excess LDL-influx leads to an eventual accumulation of neutral lipid droplets around LD-R amastigotes, thereby increasing their unresponsiveness toward Amphotericin-B, a second-line amphiphilic antileishmanial. Notably, VL patients showing relapse with Amphotericin-B treatment exhibited significantly lower serum LDL and cholesterol than cured cases. Treatment with Aspirin, a lipid droplet blocker, reduced lipid droplets around LD-R amastigotes, restoring Amphotericin-B responsiveness.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reliable protein-protein docking with AlphaFold, Rosetta, and replica exchange. 与AlphaFold， Rosetta和副本交换可靠的蛋白质对接。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-27 DOI: 10.7554/eLife.94029

Ameya Harmalkar, Sergey Lyskov, Jeffrey J Gray

{"title":"Reliable protein-protein docking with AlphaFold, Rosetta, and replica exchange.","authors":"Ameya Harmalkar, Sergey Lyskov, Jeffrey J Gray","doi":"10.7554/eLife.94029","DOIUrl":"10.7554/eLife.94029","url":null,"abstract":"Despite the recent breakthrough of AlphaFold (AF) in the field of protein sequence-to-structure prediction, modeling protein interfaces and predicting protein complex structures remains challenging, especially when there is a significant conformational change in one or both binding partners. Prior studies have demonstrated that AF-multimer (AFm) can predict accurate protein complexes in only up to 43% of cases (Yin et al., 2022). In this work, we combine AF as a structural template generator with a physics-based replica exchange docking algorithm to better sample conformational changes. Using a curated collection of 254 available protein targets with both unbound and bound structures, we first demonstrate that AF confidence measures (pLDDT) can be repurposed for estimating protein flexibility and docking accuracy for multimers. We incorporate these metrics within our ReplicaDock 2.0 protocol to complete a robust in silico pipeline for accurate protein complex structure prediction. AlphaRED (AlphaFold-initiated Replica Exchange Docking) successfully docks failed AF predictions, including 97 failure cases in Docking Benchmark Set 5.5. AlphaRED generates CAPRI acceptable-quality or better predictions for 63% of benchmark targets. Further, on a subset of antigen-antibody targets, which is challenging for AFm (20% success rate), AlphaRED demonstrates a success rate of 43%. This new strategy demonstrates the success possible by integrating deep learning-based architectures trained on evolutionary information with physics-based enhanced sampling. The pipeline is available at https://github.com/Graylab/AlphaRED.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Kv2 inhibitor combination reveals native neuronal conductances consistent with Kv2/KvS heteromers. Kv2抑制剂组合显示天然神经元电导与Kv2/ kv异构体一致。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-27 DOI: 10.7554/eLife.99410

Robert G Stewart, Matthew James Marquis, Sooyeon Jo, Brandon J Harris, Aman S Aberra, Verity Cook, Zachary Whiddon, Vladimir Yarov-Yarovoy, Michael Ferns, Jon T Sack

{"title":"A Kv2 inhibitor combination reveals native neuronal conductances consistent with Kv2/KvS heteromers.","authors":"Robert G Stewart, Matthew James Marquis, Sooyeon Jo, Brandon J Harris, Aman S Aberra, Verity Cook, Zachary Whiddon, Vladimir Yarov-Yarovoy, Michael Ferns, Jon T Sack","doi":"10.7554/eLife.99410","DOIUrl":"10.7554/eLife.99410","url":null,"abstract":"KvS proteins are voltage-gated potassium channel subunits that form functional channels when assembled into heteromers with Kv2.1 (KCNB1) or Kv2.2 (KCNB2). Mammals have 10 KvS subunits: Kv5.1 (KCNF1), Kv6.1 (KCNG1), Kv6.2 (KCNG2), Kv6.3 (KCNG3), Kv6.4 (KCNG4), Kv8.1 (KCNV1), Kv8.2 (KCNV2), Kv9.1 (KCNS1), Kv9.2 (KCNS2), and Kv9.3 (KCNS3). Electrically excitable cells broadly express channels containing Kv2 subunits and most neurons have substantial Kv2 conductance. However, whether KvS subunits contribute to these conductances has not been clear, leaving the physiological roles of KvS subunits poorly understood. Here, we identify that two potent Kv2 inhibitors, used in combination, can distinguish conductances of Kv2/KvS heteromers and Kv2-only channels. We find that Kv5, Kv6, Kv8, or Kv9-containing channels are resistant to the Kv2-selective pore-blocker RY785 yet remain sensitive to the Kv2-selective voltage sensor modulator guangxitoxin-1E (GxTX). Using these inhibitors in mouse superior cervical ganglion neurons, we find predominantly RY785-sensitive conductances consistent with channels composed entirely of Kv2 subunits. In contrast, RY785-resistant but GxTX-sensitive conductances consistent with Kv2/KvS heteromeric channels predominate in mouse and human dorsal root ganglion neurons. These results establish an approach to pharmacologically distinguish conductances of Kv2/KvS heteromers from Kv2-only channels, enabling investigation of the physiological roles of endogenous KvS subunits. These findings suggest that drugs which distinguish KvS subunits could modulate electrical activity of subsets of Kv2-expressing cell types.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comparative analysis of the syncytiotrophoblast in placenta tissue and trophoblast organoids using snRNA sequencing. 利用snRNA测序技术对胎盘组织中合胞滋养细胞和滋养细胞类器官进行比较分析。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-27 DOI: 10.7554/eLife.101170

Madeline M Keenen, Liheng Yang, Huan Liang, Veronica J Farmer, Rizban E Worota, Rohit Singh, Amy S Gladfelter, Carolyn B Coyne

{"title":"Comparative analysis of the syncytiotrophoblast in placenta tissue and trophoblast organoids using snRNA sequencing.","authors":"Madeline M Keenen, Liheng Yang, Huan Liang, Veronica J Farmer, Rizban E Worota, Rohit Singh, Amy S Gladfelter, Carolyn B Coyne","doi":"10.7554/eLife.101170","DOIUrl":"10.7554/eLife.101170","url":null,"abstract":"The syncytiotrophoblast (STB) is a multinucleated cell layer that forms the outer surface of human chorionic villi. Its unusual structure, with billions of nuclei in a single cell, makes it difficult to resolve using conventional single-cell methods. To better understand STB differentiation, we performed single-nucleus and single-cell RNA sequencing on placental tissue and trophoblast organoids (TOs). Single-nucleus RNA-seq was essential for capturing STB populations, revealing three nuclear subtypes: a juvenile subtype co-expressing CTB and STB markers, one enriched in oxygen sensing genes, and another in transport and GTPase signaling. Organoids grown in suspension culture (STBout) showed higher expression of STB markers, hormones, and a greater proportion of the transport-associated nuclear subtype while TOs grown with an inverted polarity (STBin) exhibited a higher proportion of the oxygen sensing nuclear subtype. Gene regulatory analysis identified conserved STB markers, including the chromatin remodeler RYBP. Although RYBP knockout did not impair fusion, it downregulated CSH1 and upregulated oxygen-sensing genes. Comparing STB expression in first trimester, term, and TOs revealed shared features but context-dependent variability. These findings establish TOs as a robust platform to model STB differentiation and nuclear heterogeneity, providing insight into the regulatory networks that shape placental development and function.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Optogenetic control of a GEF of RhoA uncovers a signaling switch from retraction to protrusion. 光遗传学控制RhoA的GEF揭示了从回缩到突出的信号开关。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-27 DOI: 10.7554/eLife.93180

Jean de Seze, Maud Bongaerts, Benoit Boulevard, Mathieu Coppey

{"title":"Optogenetic control of a GEF of RhoA uncovers a signaling switch from retraction to protrusion.","authors":"Jean de Seze, Maud Bongaerts, Benoit Boulevard, Mathieu Coppey","doi":"10.7554/eLife.93180","DOIUrl":"10.7554/eLife.93180","url":null,"abstract":"The ability of a single protein to trigger different functions is an assumed key feature of cell signaling, yet there are very few examples demonstrating it. Here, using an optogenetic tool to control membrane localization of RhoA nucleotide exchange factors (GEFs), we present a case where the same protein can trigger both protrusion and retraction when recruited to the plasma membrane, polarizing the cell in two opposite directions. We show that the basal concentration of the GEF prior to activation predicts the resulting phenotype. A low concentration leads to retraction, whereas a high concentration triggers protrusion. This unexpected protruding behavior arises from the simultaneous activation of Cdc42 by the GEF and sequestration of active RhoA by the GEF PH domain at high concentrations. We propose a minimal model that recapitulates the phenotypic switch, and we use its predictions to control the two phenotypes within selected cells by adjusting the frequency of light pulses. Our work exemplifies a unique case of control of antagonist phenotypes by a single protein that switches its function based on its concentration or dynamics of activity. It raises numerous open questions about the link between signaling protein and function, particularly in contexts where proteins are highly overexpressed, as often observed in cancer.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integration of head and body orientations in the macaque superior temporal sulcus is stronger for upright bodies. 直立身体的猕猴颞上沟对头部和身体方向的整合更强。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-27 DOI: 10.7554/eLife.105714

Yordanka Zafirova, Rufin Vogels

引用次数: 0

Household clustering and seasonal genetic variation of Plasmodium falciparum at the community-level in The Gambia. 冈比亚社区恶性疟原虫的家庭聚集性和季节性遗传变异

IF 6.4 1区生物学

eLife Pub Date : 2025-05-27 DOI: 10.7554/eLife.103047

Marc-Antoine Guery, Sukai Ceesay, Sainabou Drammeh, Fatou K Jaiteh, Umberto D'Alessandro, Teun Bousema, David J Conway, Antoine Claessens

{"title":"Household clustering and seasonal genetic variation of Plasmodium falciparum at the community-level in The Gambia.","authors":"Marc-Antoine Guery, Sukai Ceesay, Sainabou Drammeh, Fatou K Jaiteh, Umberto D'Alessandro, Teun Bousema, David J Conway, Antoine Claessens","doi":"10.7554/eLife.103047","DOIUrl":"10.7554/eLife.103047","url":null,"abstract":"Understanding the genetic diversity and transmission dynamics of Plasmodium falciparum, the causative agent of malaria, is crucial for effective control and elimination efforts. In some endemic regions, malaria is highly seasonal with no or little transmission during up to 8 mo, yet little is known about how seasonality affects the parasite population genetics. Here, we conducted a longitudinal study over 2.5 y on 1516 participants in the Upper River Region of The Gambia. With 425 P. falciparum genetic barcodes genotyped from asymptomatic infections, we developed an identity by descent (IBD) based pipeline and validated its accuracy against 199 parasite genomes sequenced from the same isolates. Genetic relatedness between isolates revealed a very low inbreeding level, suggesting continuous recombination among parasites rather than the dominance of specific strains. However, isolates from the same household were sixfold more likely to be genetically related compared to those from other villages, suggesting close transmission links within households. Seasonal variation also influenced parasite genetics, with most differentiation occurring during the transition from the low transmission season to the subsequent high transmission season. Yet chronic infections presented exceptions, including one individual who had a continuous infection by the same parasite genotype for at least 18 mo. Our findings highlight the burden of asymptomatic chronic malaria carriers and the importance of characterizing the parasite genetic population at the community-level. Most importantly, 'reactive' approaches for malaria elimination should not be limited to acute malaria cases but be broadened to households of asymptomatic carriers.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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