PLoS PathogensPub Date : 2025-02-03eCollection Date: 2025-02-01DOI: 10.1371/journal.ppat.1012876
Marco A Coelho, Márcia David-Palma, Janneke Aylward, Nam Q Pham, Cobus M Visagie, Taygen Fuchs, Neriman Yilmaz, Francois Roets, Sheng Sun, John W Taylor, Brenda D Wingfield, Matthew C Fisher, Michael J Wingfield, Joseph Heitman
{"title":"Decoding Cryptococcus: From African biodiversity to worldwide prevalence.","authors":"Marco A Coelho, Márcia David-Palma, Janneke Aylward, Nam Q Pham, Cobus M Visagie, Taygen Fuchs, Neriman Yilmaz, Francois Roets, Sheng Sun, John W Taylor, Brenda D Wingfield, Matthew C Fisher, Michael J Wingfield, Joseph Heitman","doi":"10.1371/journal.ppat.1012876","DOIUrl":"10.1371/journal.ppat.1012876","url":null,"abstract":"","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012876"},"PeriodicalIF":5.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Streptococcus mutans regulates ubiquitin modification of Candida albicans in the bacterial-fungal interaction.","authors":"Yixin Zhang, Zhen Gu, Zhengyi Li, Qinrui Wu, Xin Xu, Xian Peng","doi":"10.1371/journal.ppat.1012887","DOIUrl":"10.1371/journal.ppat.1012887","url":null,"abstract":"<p><p>The ecological interplay between Streptococcus mutans and Candida albicans within dental plaque biofilms is an important factor driving pathogenesis of dental caries. This study aimed to investigate S. mutans regulation of C. albicans growth and virulence through extracellular membrane vesicles (EMVs) and modulation of ubiquitination, a key protein post-translational modification. We established a transwell co-culture model to enable \"contact-independent\" interactions between S. mutans and C. albicans. S. mutans EMVs were found to directly associate with C. albicans cells and promote biofilm formation and growth. Quantitative ubiquitination profiling revealed S. mutans dramatically alters the ubiquitination landscape in C. albicans. We identified 10,661 ubiquitination sites across the C. albicans proteome and their enrichment in pathways related to translation, metabolism, and stress adaptation. Co-culture with S. mutans led to upregulation of ubiquitination on 398 proteins involved in sugar catabolism and generation of reducing power. S. mutans upregulated ubiquitination of superoxide dismutase-3 of C. albicans, inducing its degradation and heightened reactive oxygen species levels, and concomitantly stimulated C. albicans growth. Our findings elucidate EMVs and ubiquitination modulation as key mechanisms governing the S. mutans-C. albicans interplay and provide new insights into the promotion of a cariogenic oral biofilm environment. This study significantly advances understanding of the complex molecular interactions underlying dental plaque dysbiosis and caries pathogenesis.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012887"},"PeriodicalIF":5.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11838896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Marek's disease virus-1 unique gene LORF1 is involved in viral replication and MDV-1/Md5-induced atrophy of the bursa of Fabricius.","authors":"Chenyi Bao, Jun Chu, Qi Gao, Shasha Yang, Xiaoyu Gao, Wenwen Chen, Fuchun Yang, Fei Jiang, Chenxi Tong, Mingyi Lei, Linlin Jiao, Jitong Li, Kexin Wei, Xue Lian, Kai Li, Suresh Kumar Tikoo, Nikolaus Osterrieder, Lorne A Babiuk, Yufeng Li, Yong-Sam Jung, Yingjuan Qian","doi":"10.1371/journal.ppat.1012891","DOIUrl":"10.1371/journal.ppat.1012891","url":null,"abstract":"<p><p>Marek's disease virus (MDV), an alphaherpesvirus, causes severe immunosuppression and T cell lymphomas in chickens, known as Marek's disease (MD), an economically important poultry disease primarily controlled by vaccination. Importantly, it also serves as a comparative model for studying herpesvirus-induced tumor formation in humans. MDV encodes more than 100 genes, most of which have unknown functions. MDV LORF1 is unique to serotype I MDV (MDV-1), lacking homologs in other herpesviruses, and has not been explored yet. To this end, an infectious bacterial artificial chromosome (BAC) harboring the complete genome of the MDV-1 very virulent strain Md5 was generated, and the rescued rMd5 maintained biological properties similar to the parental virus both in vitro and in vivo. Subsequently, rMd5ΔLORF1, a recombinant Md5 virus deficient in pLORF1 expression, was generated by a frameshift mutation in the LORF1 gene. Chickens infected with rMd5ΔLORF1 exhibited a lower mortality rate and delayed bursal atrophy than those infected with the parental rMd5 and the revertant virus (rMd5-reLORF1). Consistently, viral loads of rMd5ΔLORF1 were obviously lower than those of rMd5 or rMd5-reLORF1 in the bursa, but not in the spleen. Importantly, we found that pLORF1 deficiency impairs viral replication in bursal B cells. Furthermore, we showed that pLORF1 associated with the cellular membrane, interacted with MDV structural proteins, and exhibited punctate colocalization with tegument or capsid proteins in the cytoplasm. Taken together, this study demonstrates for the first time that the MDV-1 unique gene LORF1 is involved in MDV-induced bursal atrophy but not in tumor formation.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012891"},"PeriodicalIF":5.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS PathogensPub Date : 2025-02-03eCollection Date: 2025-02-01DOI: 10.1371/journal.ppat.1012654
Andrew S Wagner, Frances M Smith, David A Bennin, James A Votava, Rupsa Datta, Morgan A Giese, Wenxuan Zhao, Melissa C Skala, Jing Fan, Nancy P Keller, Anna Huttenlocher
{"title":"GATA1-deficient human pluripotent stem cells generate neutrophils with improved antifungal immunity that is mediated by the integrin CD18.","authors":"Andrew S Wagner, Frances M Smith, David A Bennin, James A Votava, Rupsa Datta, Morgan A Giese, Wenxuan Zhao, Melissa C Skala, Jing Fan, Nancy P Keller, Anna Huttenlocher","doi":"10.1371/journal.ppat.1012654","DOIUrl":"10.1371/journal.ppat.1012654","url":null,"abstract":"<p><p>Neutrophils are critical for host defense against fungi. However, the short life span and lack of genetic tractability of primary human neutrophils has limited in vitro analysis of neutrophil-fungal interactions. Human induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) provide a genetically tractable system to study host defense responses of human neutrophils. Here, we show that deletion of the transcription factor GATA1 from human iPSCs results in iNeutrophils with improved antifungal activity against Aspergillus fumigatus. GATA1-knockout (KO) iNeutrophils have increased maturation, antifungal pattern recognition receptor expression and have improved neutrophil effector functions compared to wild-type iNeutrophils. iNeutrophils also show a shift in their metabolism following stimulation with fungal β-glucan to the pentose phosphate pathway (PPP), similar to primary human neutrophils. Furthermore, we show that deletion of the integrin CD18 attenuates the ability of GATA1-KO iNeutrophils to kill A. fumigatus but is not necessary for the metabolic shift. Collectively, these findings support iNeutrophils as a robust system to study human neutrophil antifungal immunity and has identified specific roles for CD18 in the defense response.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012654"},"PeriodicalIF":5.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS PathogensPub Date : 2025-02-03eCollection Date: 2025-02-01DOI: 10.1371/journal.ppat.1012857
Megan A Sloan, Adam Scott, Dana Aghabi, Lucia Mrvova, Clare R Harding
{"title":"Iron-mediated post-transcriptional regulation in Toxoplasma gondii.","authors":"Megan A Sloan, Adam Scott, Dana Aghabi, Lucia Mrvova, Clare R Harding","doi":"10.1371/journal.ppat.1012857","DOIUrl":"10.1371/journal.ppat.1012857","url":null,"abstract":"<p><p>Iron is required to support almost all life; however, levels must be carefully regulated to maintain homeostasis. Although the obligate parasite Toxoplasma gondii requires iron, how it responds upon iron limitation has not been investigated. Here, we show that iron depletion triggers significant transcriptional changes in the parasite, including in iron-dependent pathways. We find that a subset of T. gondii transcripts contain stem-loop structures, which have been associated with post-transcriptional iron-mediated regulation in other cellular systems. We validate one of these (found in the 3' UTR of TGME49_261720) using a reporter cell line. We show that the presence of the stem-loop-containing UTR is sufficient to confer accumulation at the transcript and protein levels under low iron. This response is dose and time-dependent and is specific for iron. The accumulation of transcript is likely driven by an increased reporter mRNA stability under low iron. Interestingly, we find iron-mediated changes in mRNA stability in around 400 genes. To examine the potential mechanism of this stability, we tested aconitase interaction with mRNA in low iron and found 43 enriched transcripts, but no specific interaction with our reporter UTR. However, the endogenous UTR led to maintenance of protein levels and increased survival of the parasite under low iron. Our data demonstrate the existence of iron-mediated post-transcriptional regulation in Toxoplasma for the first time; and suggests iron-mediated regulation may be important to the parasite in low iron environments.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012857"},"PeriodicalIF":5.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11801735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS PathogensPub Date : 2025-02-03eCollection Date: 2025-02-01DOI: 10.1371/journal.ppat.1012184
Emanuele G Silva, Isaque J S de Faria, Álvaro G A Ferreira, Thiago Henrique L Jiran, Carlos F Estevez-Castro, Juliana N Armache, Siad C G Amadou, Yann Verdier, Joëlle Vinh, Karim Majzoub, Carine Meignin, Gabrielle Haas, Franck Martin, Jean-Luc Imler, João T Marques
{"title":"Argonaute 2 targets viral transcripts but not genomes of RNA viruses during antiviral RNA interference in Drosophila.","authors":"Emanuele G Silva, Isaque J S de Faria, Álvaro G A Ferreira, Thiago Henrique L Jiran, Carlos F Estevez-Castro, Juliana N Armache, Siad C G Amadou, Yann Verdier, Joëlle Vinh, Karim Majzoub, Carine Meignin, Gabrielle Haas, Franck Martin, Jean-Luc Imler, João T Marques","doi":"10.1371/journal.ppat.1012184","DOIUrl":"10.1371/journal.ppat.1012184","url":null,"abstract":"<p><p>RNA interference (RNAi) mediated by the small interfering RNA (siRNA) pathway is a major antiviral mechanism in insects. This pathway is triggered when double-stranded RNA (dsRNA) produced during virus replication is recognized by Dicer-2, leading to the formation of virus-derived siRNA duplexes. These siRNAs are loaded onto the programmable nuclease Argonaute-2 (AGO2), with one strand serving as a guide to target and cleave fully complementary sequences of viral RNAs. While siRNAs are generated from viral dsRNA, the specific viral RNA species targeted for silencing during RNA virus replication remains unclear. In this study, we characterized the primary viral RNA targets of the Drosophila siRNA pathway during infections caused by negative and positive RNA viruses, namely Vesicular stomatitis virus (VSV) and Sindbis virus (SINV). Our findings reveal that polyadenylated transcripts of VSV and SINV are the major targets of silencing by the siRNA pathway during infection, likely when they are poised for translation. Consistent with earlier findings, we show that AGO2 is associated with ribosomes in control and virus infected cells. Therefore, we propose that the inhibition of the replication of RNA viruses in Drosophila results from the silencing of incoming viral transcripts, facilitated by the association of AGO2 with ribosomes.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012184"},"PeriodicalIF":5.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS PathogensPub Date : 2025-02-03eCollection Date: 2025-02-01DOI: 10.1371/journal.ppat.1012216
Mukul Rawat, Gilda Padalino, Edem Adika, John Okombo, Tomas Yeo, Andrea Brancale, David A Fidock, Karl F Hoffmann, Marcus C S Lee
{"title":"Quinoxaline-based anti-schistosomal compounds have potent anti-plasmodial activity.","authors":"Mukul Rawat, Gilda Padalino, Edem Adika, John Okombo, Tomas Yeo, Andrea Brancale, David A Fidock, Karl F Hoffmann, Marcus C S Lee","doi":"10.1371/journal.ppat.1012216","DOIUrl":"10.1371/journal.ppat.1012216","url":null,"abstract":"<p><p>The human pathogens Plasmodium and Schistosoma are each responsible for over 200 million infections annually, especially in low- and middle-income countries. There is a pressing need for new drug targets for these diseases, driven by emergence of drug-resistance in Plasmodium and an overall dearth of drug targets against Schistosoma. Here, we explored the opportunity for pathogen-hopping by evaluating a series of quinoxaline-based anti-schistosomal compounds for their activity against P. falciparum. We identified compounds with low nanomolar potency against 3D7 and multidrug-resistant strains. In vitro resistance selections using wildtype and mutator P. falciparum lines revealed a low propensity for resistance. Only one of the series, compound 22, yielded resistance mutations, including point mutations in a non-essential putative hydrolase pfqrp1, as well as copy number amplification of a phospholipid-translocating ATPase, pfatp2, a potential target. Notably, independently generated CRISPR-edited mutants in pfqrp1 also showed resistance to compound 22 and a related analogue. Moreover, previous lines with pfatp2 copy number variations were similarly less susceptible to challenge with the new compounds. Finally, we examined whether the predicted hydrolase activity of PfQRP1 underlies its mechanism of resistance, showing that both mutation of the putative catalytic triad and a more severe loss of function mutation elicited resistance. Collectively, we describe a compound series with potent activity against two important pathogens and their potential target in P. falciparum.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012216"},"PeriodicalIF":5.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS PathogensPub Date : 2025-01-31eCollection Date: 2025-01-01DOI: 10.1371/journal.ppat.1012692
Erick O Awuoche, Gretchen Smallenberger, Daniel L Bruzzese, Alessandra Orfano, Brian L Weiss, Serap Aksoy
{"title":"Spiroplasma endosymbiont reduction of host lipid synthesis and Stomoxyn-like peptide contribute to trypanosome resistance in the tsetse fly Glossina fuscipes.","authors":"Erick O Awuoche, Gretchen Smallenberger, Daniel L Bruzzese, Alessandra Orfano, Brian L Weiss, Serap Aksoy","doi":"10.1371/journal.ppat.1012692","DOIUrl":"10.1371/journal.ppat.1012692","url":null,"abstract":"<p><p>Tsetse flies (Glossina spp.) vector African trypanosomes that cause devastating diseases in humans and domestic animals. Within the Glossina genus, species in the Palpalis subgroup exhibit greater resistance to trypanosome infections compared to those in the Morsitans subgroup. Varying microbiota composition and species-specific genetic traits can significantly influence the efficiency of parasite transmission. Notably, infections with the endosymbiotic bacterium Spiroplasma have been documented in several Palpalis subgroup species, including Glossina fuscipes fuscipes (Gff). While Spiroplasma infections in Gff are known to hinder trypanosome transmission, the underlying mechanisms remain unknown. To investigate Spiroplasma-mediated factors affecting Gff vector competence, we conducted high-throughput RNA sequencing of the gut tissue along with functional assays. Our findings reveal elevated oxidative stress in the gut environment in the presence of Spiroplasma, evidenced by increased expression of nitric oxide synthase, which catalyzes the production of trypanocidal nitric oxide. Additionally, we observed impaired lipid biosynthesis leading to a reduction of this important class of nutrients essential for parasite and host physiologies. In contrast, trypanosome infections in Gff's midgut significantly upregulated various immunity-related genes, including a small peptide, Stomoxyn-like, homologous to Stomoxyn first discovered in the stable fly, Stomoxys calcitrans. We observed that the Stomoxyn-like locus is exclusive to the genomes of Palpalis subgroup tsetse species. GffStomoxyn is constitutively expressed in the cardia (proventriculus) and synthetic GffStomoxyn exhibits potent activity against Escherichia coli and bloodstream form of Trypanosoma brucei parasites, while showing no effect against insect stage procyclic forms or tsetse's commensal endosymbiont Sodalis in vitro. Reducing GffStomoxyn levels significantly increased trypanosome infection prevalence, indicating its potential trypanocidal role in vivo. Collectively, our results suggest that the enhanced resistance to trypanosomes observed in Spiroplasma-infected Gff may be due to the reduced lipid availability necessary for parasite metabolic maintenance. Furthermore, GffStomoxyn could play a crucial role in the initial immune response(s) against mammalian parasites early in the infection process in the gut and prevent gut colonization. We discuss the molecular characteristics of GffStomoxyn, its spatial and temporal expression regulation and its microbicidal activity against Trypanosome parasites. Our findings reinforce the nutritional influences of microbiota on host physiology and host-pathogen dynamics.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012692"},"PeriodicalIF":5.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11819587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pair combinations of human monoclonal antibodies fully protected mice against bunyavirus SFTSV lethal challenge.","authors":"Bang Li, Xiang-Rong Qin, Jia-Chen Qu, Guan-du Wu, Wen-Kang Zhang, Ze-Zheng Jiang, Pan-Pan Liu, Ze-Min Li, Tian-Mei Yu, Chuan-Min Zhou, Yong-Jun Jiao, Xue-Jie Yu","doi":"10.1371/journal.ppat.1012889","DOIUrl":"10.1371/journal.ppat.1012889","url":null,"abstract":"<p><p>Severe fever with thrombocytopenia syndrome (SFTS) is a viral hemorrhagic fever caused by a tick-borne virus SFTSV with a mortality rate of up to 30%. Currently, there is no vaccine or effective therapy for SFTS. Neutralizing monoclonal antibody therapy, which provides immediate passive immunity and may limit disease progression, has emerged as a reliable approach for developing therapeutic drugs for SFTS. In this study, 4 human monoclonal antibodies (hmAbs) derived from convalescent SFTS patients' lymphocytes based on human single-chain variable fragment antibody libraries were tested for their neutralizing activities in cells and their treatment effect in animals individually and in pair combinations. The neutralization test showed that all 4 hmAbs exhibited strong neutralizing activity against SFTSV infection in vitro. The protection rate of hmAbs 4-6, 1F6, 1B2, and 4-5 against SFTSV lethal challenge in IFNAR1-/- A129 mice are 50%, 16.7%, 83.3%, and 66.7%, respectively. Notably, the pair combination of antibodies (1B2 and 4-5, 1B2 and 1F6) that recognized distinct epitopes protected 100% of mice against SFTSV lethal challenge. In conclusion, our findings indicate that the pair combinations of hmAbs 1B2 and 4-5 or hmAbs 1B2 and 1F6 may serve as promising therapeutic drugs for treating SFTSV infection.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012889"},"PeriodicalIF":5.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection.","authors":"Souradeepa Ghosh, Krishna Vamshi Chigicherla, Shirin Dasgupta, Yasuyuki Goto, Budhaditya Mukherjee","doi":"10.1371/journal.ppat.1012858","DOIUrl":"10.1371/journal.ppat.1012858","url":null,"abstract":"<p><p>Despite the withdrawal of pentavalent-antimonials in treating Visceral leishmaniasis from India, recent clinical isolates of Leishmania donovani (LD) exhibit unresponsiveness towards pentavalent-antimony (LD-R). This antimony-unresponsiveness points towards a genetic adaptation that underpins LD-R's evolutionary persistence and dominance over sensitive counterparts (LD-S). This study highlights how LD evolutionarily tackled antimony exposure and gained increased potential of scavenging host-iron within its parasitophorous vacuoles (PV) to support its aggressive proliferation. Even though anti-leishmanial activity of pentavalent antimonials relies on triggering oxidative outburst, LD-R exhibits a surprising strategy of promoting reactive oxygen species (ROS) generation in infected macrophages. An inherent metabolic shift from glycolysis to Pentose Phosphate shunt allows LD-R to withstand elevated ROS by sustaining heightened levels of NADPH. Elevated ROS levels on the other hand trigger excess iron production, and LD-R capitalizes on this surplus iron by selectively reshuffling macrophage-surface iron exporter, Ferroportin, around its PV thereby gaining a survival edge as a heme-auxotroph. Higher iron utilization by LD-R leads to subsequent iron insufficiency, compensated by increased erythrophagocytosis through the breakdown of SIRPα-CD47 surveillance, orchestrated by a complex interplay of two proteases, Furin and ADAM10. Understanding these mechanisms is crucial for managing LD-R-infections and their associated complications like severe anemia, and may also provide valuable mechanistic insights into understanding drug unresponsiveness developed in other intracellular pathogens that rely on host iron.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012858"},"PeriodicalIF":5.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}