PLoS Pathogens最新文献

{"title":"Human cytomegalovirus RNA2.7 inhibits ferroptosis by upregulating ferritin and GSH via promoting ZNF395 degradation.","authors":"Mingyi Xu, Shan Ruan, Jingxuan Sun, Jianming Li, Dan Chen, Yanping Ma, Ying Qi, Zhongyang Liu, Qiang Ruan, Yujing Huang","doi":"10.1371/journal.ppat.1012815","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012815","url":null,"abstract":"<p><p>Human cytomegalovirus (HCMV) is a herpes virus with a long replication cycle. HCMV encoded long non-coding RNA termed RNA2.7 is the dominant transcript with a length of about 2.5kb, accounting for 25% of total viral transcripts. Studies have shown that HCMV RNA2.7 inhibits apoptosis caused by infection. The effect of RNA2.7 on other forms of cell death is still unclear. In this work, we found that RNA2.7 deletion significantly decreased the viability of HCMV-infected cells, while treatment with ferroptosis inhibitor Fer-1 rescued the infection-induced cell death, demonstrating an anti-ferroptosis role of RNA2.7. The results further showed that RNA2.7 inhibited ferroptosis via enhancing Ferritin Heavy Chain 1 (FTH1) and Solute Carrier Family 7 Member 11 (SLC7A11) expression in Erastin treated cells without involving other viral components. Pooled Genome-wide CRISPR screening revealed zinc finger protein 395 (ZNF395) as a new regulator repressing the expression of FTH1 and SLC7A11. HCMV RNA2.7 promoted proteasome-mediated degradation of ZNF395 that resulted in upregulation of FTH1 and SLC7A11 to inhibit ferroptosis, therefore maintain survival in host cells and complete replication of virus.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012815"},"PeriodicalIF":5.5,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pseudoknot region and poly-(C) tract comprise an essential RNA packaging signal for assembly of foot-and-mouth disease virus.","authors":"Chris Neil, Joseph Newman, Nicola J Stonehouse, David J Rowlands, Graham J Belsham, Tobias J Tuthill","doi":"10.1371/journal.ppat.1012283","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012283","url":null,"abstract":"<p><p>Virus assembly is a crucial step for the completion of the viral replication cycle. In addition to ensuring efficient incorporation of viral genomes into nascent virions, high specificity is required to prevent incorporation of host nucleic acids. For picornaviruses, including FMDV, the mechanisms required to fulfil these requirements are not well understood. However, recent evidence has suggested that specific RNA sequences dispersed throughout picornavirus genomes are involved in packaging. Here, we have shown that such sequences are essential for FMDV RNA packaging and have demonstrated roles for both the pseudoknot (PK) region and the poly-(C) tract in this process, where the length of the poly-(C) tract was found to influence the efficiency of RNA encapsidation. Sub-genomic replicons containing longer poly-(C) tracts were packaged with greater efficiency in trans, and viruses recovered from transcripts containing short poly-(C) tracts were found to have greatly extended poly-(C) tracts after only a single passage in cells, suggesting that maintaining a long poly-(C) tract provides a selective advantage. We also demonstrated a critical role for a packaging signal (PS) located in the pseudoknot (PK) region, adjacent to the poly-(C) tract, as well as several other non-essential but beneficial PSs elsewhere in the genome. Collectively, these PSs greatly enhanced encapsidation efficiency, with the poly-(C) tract possibly facilitating nearby PSs to adopt the correct conformation. Using these data, we have proposed a model where interactions with capsid precursors control a transition between two RNA conformations, directing the fate of nascent genomes to either be packaged or alternatively to act as templates for replication and/or for protein translation.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012283"},"PeriodicalIF":5.5,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic assessment of COVID-19 host genetics using whole genome sequencing data.","authors":"Axel Schmidt, Nicolas Casadei, Fabian Brand, German Demidov, Elaheh Vojgani, Ayda Abolhassani, Rana Aldisi, Guillaume Butler-Laporte, T Madhusankha Alawathurage, Max Augustin, Robert Bals, Carla Bellinghausen, Marc Moritz Berger, Michael Bitzer, Christian Bode, Jannik Boos, Thorsten Brenner, Oliver A Cornely, Thomas Eggermann, Johanna Erber, Torsten Feldt, Christian Fuchsberger, Julien Gagneur, Siri Göpel, Tobias Haack, Helene Häberle, Frank Hanses, Julia Heggemann, Ute Hehr, Johannes C Hellmuth, Christian Herr, Anke Hinney, Per Hoffmann, Thomas Illig, Björn-Erik Ole Jensen, Verena Keitel, Sarah Kim-Hellmuth, Philipp Koehler, Ingo Kurth, Anna-Lisa Lanz, Eicke Latz, Clara Lehmann, Tom Luedde, Carlo Maj, Michael Mian, Abigail Miller, Maximilian Muenchhoff, Isabell Pink, Ulrike Protzer, Hana Rohn, Jan Rybniker, Federica Scaggiante, Anna Schaffeldt, Clemens Scherer, Maximilian Schieck, Susanne V Schmidt, Philipp Schommers, Christoph D Spinner, Maria J G T Vehreschild, Thirumalaisamy P Velavan, Sonja Volland, Sibylle Wilfling, Christof Winter, J Brent Richards, André Heimbach, Kerstin Becker, Stephan Ossowski, Joachim L Schultze, Peter Nürnberg, Markus M Nöthen, Susanne Motameny, Michael Nothnagel, Olaf Riess, Eva C Schulte, Kerstin U Ludwig","doi":"10.1371/journal.ppat.1012786","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012786","url":null,"abstract":"<p><p>Courses of SARS-CoV-2 infections are highly variable, ranging from asymptomatic to lethal COVID-19. Though research has shown that host genetic factors contribute to this variability, cohort-based joint analyses of variants from the entire allelic spectrum in individuals with confirmed SARS-CoV-2 infections are still lacking. Here, we present the results of whole genome sequencing in 1,220 mainly vaccine-naïve individuals with confirmed SARS-CoV-2 infection, including 827 hospitalized COVID-19 cases. We observed the presence of autosomal-recessive or likely compound heterozygous monogenic disorders in six individuals, all of which were hospitalized and significantly younger than the rest of the cohort. We did not observe any suggestive causal variants in or around the established risk gene TLR7. Burden testing in the largest population subgroup (i.e., Europeans) suggested nominal enrichments of rare variants in coding and non-coding regions of interferon immune response genes in the overall analysis and male subgroup. Case-control analyses of more common variants confirmed associations with previously reported risk loci, with the key locus at 3p21 reaching genome-wide significance. Polygenic scores accurately captured risk in an age-dependent manner. By enabling joint analyses of different types of variation across the entire frequency spectrum, this data will continue to contribute to the elucidation of COVID-19 etiology.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012786"},"PeriodicalIF":5.5,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Nanosota-EB1 and -EB2 as Novel Nanobody Inhibitors Against Ebola Virus Infection.","authors":"Fan Bu, Gang Ye, Kimberly Morsheimer, Alise Mendoza, Hailey Turner-Hubbard, Morgan Herbst, Benjamin Spiller, Brian E Wadzinski, Brett Eaton, Manu Anantpadma, Ge Yang, Bin Liu, Robert Davey, Fang Li","doi":"10.1371/journal.ppat.1012817","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012817","url":null,"abstract":"<p><p>The Ebola filovirus (EBOV) poses a serious threat to global health and national security. Nanobodies, a type of single-domain antibody, have demonstrated promising therapeutic potential. We identified two anti-EBOV nanobodies, Nanosota-EB1 and Nanosota-EB2, which specifically target the EBOV glycoprotein (GP). Cryo-EM and biochemical data revealed that Nanosota-EB1 binds to the glycan cap of GP1, preventing its protease cleavage, while Nanosota-EB2 binds to critical membrane-fusion elements in GP2, stabilizing it in the pre-fusion state. Nanosota-EB2 is a potent neutralizer of EBOV infection in vitro and offers excellent protection in a mouse model of EBOV challenge, while Nanosota-EB1 provides moderate neutralization and protection. Nanosota-EB1 and Nanosota-EB2 are the first nanobodies shown to inhibit authentic EBOV. Combined with our newly developed structure-guided in vitro evolution approach, they lay the foundation for nanobody-based therapies against EBOV and other viruses within the ebolavirus genus.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012817"},"PeriodicalIF":5.5,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stress contingent changes in Hog1 pathway architecture and regulation in Candida albicans.","authors":"Alison M Day, Min Cao, Alessandra da Silva Dantas, Olga Ianieva, Carmen Herrero-de-Dios, Alistair J P Brown, Janet Quinn","doi":"10.1371/journal.ppat.1012314","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012314","url":null,"abstract":"<p><p>The Hog1 stress-activated protein kinase (SAPK) is a key mediator of stress resistance and virulence in Candida albicans. Hog1 activation via phosphorylation of the canonical TGY motif is mediated by the Pbs2 MAPKK, which itself is activated by the Ssk2 MAPKKK. Although this three-tiered SAPK signalling module is well characterised, it is unclear how Hog1 activation is regulated in response to different stresses. Functioning upstream of the Ssk2 MAPKKK is a two-component related signal transduction system comprising three sensor histidine kinases, a phosphotransfer protein Ypd1, and a response regulator Ssk1. Here, we report that Ssk1 is a master regulator of the Hog1 SAPK that promotes stress resistance and Hog1 phosphorylation in response to diverse stresses, except high osmotic stress. Notably, we find Ssk1 regulates Hog1 in a two-component independent manner by functioning to promote interactions between the Ssk2 and Pbs2 kinases. We propose this function of Ssk1 is important to maintain a basal level of Hog1 phosphorylation which is necessary for oxidative stress, but not osmotic stress, mediated Hog1 activation. We find that osmotic stress triggers robust Pbs2 phosphorylation which drives its dissociation from Ssk2. In contrast, Pbs2 is not robustly phosphorylated following oxidative stress and the Ssk1-mediated Ssk2-Pbs2 interaction remains intact. Instead, oxidative stress-stimulated increases in phosphorylated Hog1 is dependent on the inhibition of protein tyrosine phosphatases that negatively regulate Hog1 coupled with the Ssk1-mediated promotion of basal Hog1 activity. Furthermore, we find that inhibition of protein tyrosine phosphatases is linked to the hydrogen peroxide induced oxidation of these negative regulators in a mechanism that is partly dependent on thioredoxin. Taken together these data reveal stress contingent changes in Hog1 pathway architecture and regulation and uncover a novel mode of action of the Ssk1 response regulator in SAPK regulation.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012314"},"PeriodicalIF":5.5,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunodominant extracellular loops of Treponema pallidum FadL outer membrane proteins elicit antibodies with opsonic and growth-inhibitory activities.","authors":"Kristina N Delgado, Melissa J Caimano, Isabel C Orbe, Crystal F Vicente, Carson J La Vake, André A Grassmann, M Anthony Moody, Justin D Radolf, Kelly L Hawley","doi":"10.1371/journal.ppat.1012443","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012443","url":null,"abstract":"<p><p>The global resurgence of syphilis has created a potent stimulus for vaccine development. To identify potentially protective antibodies against Treponema pallidum (TPA), we used Pyrococcus furiosus thioredoxin (PfTrx) to display extracellular loops (ECLs) from three TPA outer membrane protein families (outer membrane factors for efflux pumps, eight-stranded β-barrels, and FadLs) to assess their reactivity with immune rabbit serum (IRS). We identified five immunodominant loops from the FadL orthologs TP0856, TP0858 and TP0865 by immunoblotting and ELISA. Rabbits and mice immunized with these five PfTrx constructs produced loop-specific antibodies that promoted opsonophagocytosis of TPA by rabbit peritoneal and murine bone marrow-derived macrophages at levels comparable to IRS and mouse syphilitic serum. Heat-inactivated IRS and loop-specific rabbit and mouse antisera also impaired viability, motility, and cellular attachment of spirochetes during in vitro cultivation. The results support the use of ECL-based vaccines and suggest that loop-specific antibodies promote spirochete clearance via Fc receptor-independent as well as Fc receptor-dependent mechanisms.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012443"},"PeriodicalIF":5.5,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural insights into Semiliki forest virus receptor binding modes indicate novel mechanism of virus endocytosis.","authors":"Decheng Yang, Nan Wang, Bingchen Du, Zhenzhao Sun, Shida Wang, Xijun He, Jinyue Wang, Tao Zheng, Yutao Chen, Xiangxi Wang, Jingfei Wang","doi":"10.1371/journal.ppat.1012770","DOIUrl":"10.1371/journal.ppat.1012770","url":null,"abstract":"<p><p>The Very Low-Density Lipoprotein Receptor (VLDLR) is an entry receptor for the prototypic alphavirus Semliki Forest Virus (SFV). However, the precise mechanisms underlying the entry of SFV into cells mediated by VLDLR remain unclear. In this study, we found that of the eight class A (LA) repeats of the VLDLR, only LA2, LA3, and LA5 specifically bind to the native SFV virion while synergistically promoting SFV cell attachment and entry. Furthermore, the multiple cryo-electron microscopy structures of VLDLR-SFV complexes and mutagenesis studies have demonstrated that under physiological conditions, VLDLR primarily binds to E1-DIII of site-1, site-2, and site-1' at the twofold symmetry axes of SFV virion through LA2, LA3, and LA5, respectively. These findings unveil a novel mechanism for viral entry mediated by receptors, suggesting that conformational transitions in VLDLR induced by multivalent binding of LAs facilitate cellular internalization of SFV, with significant implications for the design of antiviral therapeutics.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012770"},"PeriodicalIF":5.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869667","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":"Macrophage MST1 protects against schistosomiasis-induced liver fibrosis by promoting the PPARγ-CD36 pathway and suppressing NF-κB signaling.","authors":"Jianyang Li, Xinyuan Cai, Yan Yang, Yulin Mao, Lin Ding, Qian Xue, Xunhao Hu, Yan Huang, Cong Sui, Yuxia Zhang","doi":"10.1371/journal.ppat.1012790","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012790","url":null,"abstract":"<p><p>Schistosomiasis is characterized by egg-induced hepatic granulomas and subsequent fibrosis. Monocyte-derived macrophages play critical and plastic roles in the progression and regression of liver fibrosis, adopting different polarization phenotypes. Mammalian STE20-like protein kinase 1 (MST1), a serine/threonine kinase, has been established to act as a negative regulator of macrophage-associated inflammation. However, the specific role of MST1 in Schistosoma-induced liver fibrosis has not been fully understood. In this study, we demonstrate that macrophage MST1 functions as an inhibitor of inflammation and fibrosis following infection with Schistosoma japonicum (S. japonicum). Mice with macrophages-specific Mst1 knockout (termed Mst1△M/△M) mice developed exacerbated liver pathology, characterized by larger egg-induced granulomas, and increased fibrosis post infection. This was accompanied by enhanced production of proinflammatory cytokines (IL1B, IL6, IL23, TNFA and TGFB) and a shift in macrophage phenotype towards Ly6Chigh. Mechanistically, MST1 activation by soluble egg antigen (SEA) promoted PPARγ-mediated CD36 expression, enhancing phagocytosis and consequently upregulation of fibrolytic genes such as Arg1 and Mmps. Conversely, MST1 deletion leads to up-regulation of pro-inflammatory genes instead of fibrolytic genes in macrophages, accompanied by decreased expression of CD36 and impaired phagocytosis. Furthermore, the ablation of MST1 enhances NF-κB activation in S. japonicum-infected and SEA-stimulated macrophages, resulting in increased production of proinflammatory cytokines. Overall, our data identified MST1 as a novel regulator for egg-induced liver fibrosis via modulation of macrophage function and phenotype by CD36-mediated phagocytosis and suppression of NF-κB pathway.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012790"},"PeriodicalIF":5.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APEX-based proximity labeling in Plasmodium identifies a membrane protein with dual functions during mosquito infection.","authors":"Jessica Kehrer, Emma Pietsch, Dominik Ricken, Léanne Strauss, Julia M Heinze, Tim Gilberger, Friedrich Frischknecht","doi":"10.1371/journal.ppat.1012788","DOIUrl":"10.1371/journal.ppat.1012788","url":null,"abstract":"<p><p>Transmission of the malaria parasite Plasmodium to mosquitoes necessitates gamete egress from red blood cells to allow zygote formation and ookinete motility to enable penetration of the midgut epithelium. Both processes are dependent on the secretion of proteins from distinct sets of specialized vesicles. Inhibiting some of these proteins has shown potential for blocking parasite transmission to the mosquito. To identify new transmission blocking vaccine candidates, we aimed to define the microneme content from ookinetes of the rodent model organism Plasmodium berghei using APEX2-mediated rapid proximity-dependent biotinylation. Besides known proteins of ookinete micronemes, this identified over 50 novel candidates and sharpened the list of a previous survey based on subcellular fractionation. Functional analysis of a first candidate uncovered a dual role for this membrane protein in male gametogenesis and ookinete midgut traversal. Mutation of a putative trafficking motif in the C-terminus affected ookinete to oocyst transition but not gamete formation. This suggests the existence of distinct functional and transport requirements for Plasmodium proteins in different parasite stages.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012788"},"PeriodicalIF":5.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856245","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":"Immunopeptidomic MHC-I profiling and immunogenicity testing identifies Tcj2 as a new Chagas disease mRNA vaccine candidate.","authors":"Leroy Versteeg, Rakesh Adhikari, Gonteria Robinson, Jungsoon Lee, Junfei Wei, Nelufa Islam, Brian Keegan, William K Russell, Cristina Poveda, Maria Jose Villar, Kathryn Jones, Maria Elena Bottazzi, Peter Hotez, Edwin Tijhaar, Jeroen Pollet","doi":"10.1371/journal.ppat.1012764","DOIUrl":"10.1371/journal.ppat.1012764","url":null,"abstract":"<p><p>Trypanosoma cruzi is a protozoan parasite that causes Chagas disease. Globally 6 to 7 million people are infected by this parasite of which 20-30% will progress to develop Chronic Chagasic Cardiomyopathy (CCC). Despite its high disease burden, no clinically approved vaccine exists for the prevention or treatment of CCC. Developing vaccines that can stimulate T. cruzi-specific CD8+ cytotoxic T cells and eliminate infected cells requires targeting parasitic antigens presented on major histocompatibility complex-I (MHC-I) molecules. We utilized mass spectrometry-based immunopeptidomics to investigate which parasitic peptides are displayed on MHC-I of T. cruzi infected cells. Through duplicate experiments, we identified an array of unique peptides that could be traced back to 17 distinct T. cruzi proteins. Notably, six peptides were derived from Tcj2, a trypanosome chaperone protein and member of the DnaJ (heat shock protein 40) family, showcasing its potential as a viable candidate vaccine antigen with cytotoxic T cell inducing capacity. Upon testing Tcj2 as an mRNA vaccine candidate in mice, we observed a strong memory cytotoxic CD8+ T cell response along with a Th1-skewed humoral antibody response. In vitro co-cultures of T. cruzi infected cells with splenocytes of Tcj2-immunized mice restricted the replication of T. cruzi, demonstrating the protective potential of Tcj2 as a vaccine target. Moreover, antisera from Tcj2-vaccinated mice displayed no cross-reactivity with DnaJ in lysates from mouse and human indicating a decreased likelihood of triggering autoimmune reactions. Our findings highlight how immunopeptidomics can identify new vaccine targets for Chagas disease, with Tcj2 emerging as a promising new mRNA vaccine candidate.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012764"},"PeriodicalIF":5.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11654963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856262","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}