PLoS Pathogens最新文献

Turning the needle into the haystack: Culture-independent amplification of complex microbial genomes directly from their native environment 大海捞针：不依赖培养基，直接从原生环境中扩增复杂微生物基因组

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2024-09-12 DOI: 10.1371/journal.ppat.1012418

Olivia A. Pilling, Sesh A. Sundararaman, Dustin Brisson, Daniel P. Beiting

引用次数: 0

α-Synuclein strain propagation is independent of cellular prion protein expression in a transgenic synucleinopathy mouse model 在转基因突触核蛋白病小鼠模型中，α-突触核蛋白菌株的传播与细胞朊病毒蛋白的表达无关

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2024-09-12 DOI: 10.1371/journal.ppat.1012517

Raphaella W. L. So, Genki Amano, Erica Stuart, Aeen Ebrahim Amini, Adriano Aguzzi, Graham L. Collingridge, Joel C. Watts

{"title":"α-Synuclein strain propagation is independent of cellular prion protein expression in a transgenic synucleinopathy mouse model","authors":"Raphaella W. L. So, Genki Amano, Erica Stuart, Aeen Ebrahim Amini, Adriano Aguzzi, Graham L. Collingridge, Joel C. Watts","doi":"10.1371/journal.ppat.1012517","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012517","url":null,"abstract":"The cellular prion protein, PrPC, has been postulated to function as a receptor for α-synuclein, potentially facilitating cell-to-cell spreading and/or toxicity of α-synuclein aggregates in neurodegenerative disorders such as Parkinson’s disease. Previously, we generated the “Salt (S)” and “No Salt (NS)” strains of α-synuclein aggregates that cause distinct pathological phenotypes in M83 transgenic mice overexpressing A53T-mutant human α-synuclein. To test the hypothesis that PrPC facilitates the propagation of α-synuclein aggregates, we produced M83 mice that either express or do not express PrPC. Following intracerebral inoculation with the S or NS strain, the absence of PrPC in M83 mice did not prevent disease development and had minimal influence on α-synuclein strain-specified attributes such as the extent of cerebral α-synuclein deposition, selective targeting of specific brain regions and cell types, the morphology of induced α-synuclein deposits, and the structural fingerprints of protease-resistant α-synuclein aggregates. Likewise, there were no appreciable differences in disease manifestation between PrPC-expressing and PrPC-lacking M83 mice following intraperitoneal inoculation of the S strain. Interestingly, intraperitoneal inoculation with the NS strain resulted in two distinct disease phenotypes, indicative of α-synuclein strain evolution, but this was also independent of PrPC expression. Overall, these results suggest that PrPC plays at most a minor role in the propagation, neuroinvasion, and evolution of α-synuclein strains in mice that express A53T-mutant human α-synuclein. Thus, other putative receptors or cell-to-cell propagation mechanisms may have a larger effect on the spread of α-synuclein aggregates during disease.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202232","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}

引用次数: 0

Drivers of diversification in fungal pathogen populations 真菌病原体种群多样化的驱动因素

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2024-09-12 DOI: 10.1371/journal.ppat.1012430

Daniel Murante, Deborah Ann Hogan

{"title":"Drivers of diversification in fungal pathogen populations","authors":"Daniel Murante, Deborah Ann Hogan","doi":"10.1371/journal.ppat.1012430","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012430","url":null,"abstract":"To manage and treat chronic fungal diseases effectively, we require an improved understanding of their complexity. There is an increasing appreciation that chronic infection populations are often heterogeneous due to diversification and drift, even within a single microbial species. Genetically diverse populations can contribute to persistence and resistance to treatment by maintaining cells with different phenotypes capable of thriving in these dynamic environments. In chronic infections, fungal pathogens undergo prolonged challenges that can drive trait selection to convergent adapted states through restricted access to critical nutrients, assault by immune effectors, competition with other species, and antifungal drugs. This review first highlights the various genetic and epigenetic mechanisms that promote diversity in pathogenic fungal populations and provide an additional barrier to assessing the actual heterogeneity of fungal infections. We then review existing studies of evolution and genetic heterogeneity in fungal populations from lung infections associated with the genetic disease cystic fibrosis. We conclude with a discussion of open research questions that, once answered, may aid in diagnosing and treating chronic fungal infections.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202231","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}

引用次数: 0

Glaesserella parasuis serotype 4 exploits fibronectin via RlpA for tracheal colonization following porcine circovirus type 2 infection 猪 2 型圆环病毒感染后，寄生虫 4 号血清型通过 RlpA 利用纤维粘连蛋白进行气管定植

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2024-09-12 DOI: 10.1371/journal.ppat.1012513

Mengru Guo, Yuhui Li, Jinsheng Tang, Qing Wang, Qiancheng Wang, Hong Zhou, Huixing Lin, Zhe Ma, Hongjie Fan

{"title":"Glaesserella parasuis serotype 4 exploits fibronectin via RlpA for tracheal colonization following porcine circovirus type 2 infection","authors":"Mengru Guo, Yuhui Li, Jinsheng Tang, Qing Wang, Qiancheng Wang, Hong Zhou, Huixing Lin, Zhe Ma, Hongjie Fan","doi":"10.1371/journal.ppat.1012513","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012513","url":null,"abstract":"Porcine circovirus type 2 (PCV2) often causes disease through coinfection with other bacterial pathogens, including Glaesserella parasuis (G. parasuis), which causes high morbidity and mortality, but the role played by PCV2 and bacterial and host factors contributing to this process have not been defined. Bacterial attachment is assumed to occur via specific receptor-ligand interactions between adhesins on the bacterial cell and host proteins adsorbed to the implant surface. Mass spectrometry (MS) analysis of PCV2-infected swine tracheal epithelial cells (STEC) revealed that the expression of Extracellular matrix protein (ECM) Fibronectin (Fn) increased significantly on the infected cells surface. Importantly, efficient G. parasuis serotype 4 (GPS4) adherence to STECs was imparted by interactions with Fn. Furthermore, abrogation of adherence was gained by genetic knockout of Fn, Fn and Integrin β1 antibody blocking. Fn is frequently exploited as a receptor for bacterial pathogens. To explore the GPS4 adhesin that interacts with Fn, recombinant Fn N-terminal type I and type II domains were incubated with GPS4, and the interacting proteins were pulled down for MS analysis. Here, we show that rare lipoprotein A (RlpA) directly interacts with host Fibronectin mediating GPS4 adhesion. Finally, we found that PCV2-induced Fibronectin expression and adherence of GPS4 were prevented significantly by TGF-β signaling pathway inhibitor SB431542. Our data suggest the RlpA-Fn interaction to be a potentially promising novel therapeutic target to combat PCV2 and GPS4 coinfection.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202214","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}

引用次数: 0

Elasticity of the HIV-1 core facilitates nuclear entry and infection HIV-1 核心的弹性有助于核进入和感染

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2024-09-11 DOI: 10.1371/journal.ppat.1012537

Akshay Deshpande, Alexander J. Bryer, Jonathan R. Andino-Moncada, Jiong Shi, Jun Hong, Cameron Torres, Shimon Harel, Ashwanth C. Francis, Juan R. Perilla, Christopher Aiken, Itay Rousso

{"title":"Elasticity of the HIV-1 core facilitates nuclear entry and infection","authors":"Akshay Deshpande, Alexander J. Bryer, Jonathan R. Andino-Moncada, Jiong Shi, Jun Hong, Cameron Torres, Shimon Harel, Ashwanth C. Francis, Juan R. Perilla, Christopher Aiken, Itay Rousso","doi":"10.1371/journal.ppat.1012537","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012537","url":null,"abstract":"HIV-1 infection requires passage of the viral core through the nuclear pore of the cell, a process that depends on functions of the viral capsid. Recent studies have shown that HIV-1 cores enter the nucleus prior to capsid disassembly. Interactions of the viral capsid with the nuclear pore complex are necessary but not sufficient for nuclear entry, and the mechanism by which the viral core traverses the comparably sized nuclear pore is unknown. Here we show that the HIV-1 core is highly elastic and that this property is linked to nuclear entry and infectivity. Using atomic force microscopy-based approaches, we found that purified wild type cores rapidly returned to their normal conical morphology following a severe compression. Results from independently performed molecular dynamic simulations of the mature HIV-1 capsid also revealed its elastic property. Analysis of four HIV-1 capsid mutants that exhibit impaired nuclear entry revealed that the mutant viral cores are brittle. Adaptation of two of the mutant viruses in cell culture resulted in additional substitutions that restored elasticity and rescued infectivity and nuclear entry. We also show that capsid-targeting compound PF74 and the antiviral drug Lenacepavir reduce core elasticity and block HIV-1 nuclear entry at concentrations that preserve interactions between the viral core and the nuclear envelope. Our results indicate that elasticity is a fundamental property of the HIV-1 core that enables nuclear entry, thereby facilitating infection. These results provide new insights into the role of the capsid in HIV-1 nuclear entry and the antiviral mechanisms of HIV-1 capsid inhibitors.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202265","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}

引用次数: 0

Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal 从超级延长复合体中释放 P-TEFb 可促进 HIV-1 潜伏期逆转

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2024-09-11 DOI: 10.1371/journal.ppat.1012083

William J. Cisneros, Shimaa H. A. Soliman, Miriam Walter, Lacy M. Simons, Daphne Cornish, Simone De Fabritiis, Ariel W. Halle, Eun-Young Kim, Steven M. Wolinsky, Ramon Lorenzo-Redondo, Ali Shilatifard, Judd F. Hultquist

{"title":"Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal","authors":"William J. Cisneros, Shimaa H. A. Soliman, Miriam Walter, Lacy M. Simons, Daphne Cornish, Simone De Fabritiis, Ariel W. Halle, Eun-Young Kim, Steven M. Wolinsky, Ramon Lorenzo-Redondo, Ali Shilatifard, Judd F. Hultquist","doi":"10.1371/journal.ppat.1012083","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012083","url":null,"abstract":"The persistence of HIV-1 in long-lived latent reservoirs during suppressive antiretroviral therapy (ART) remains one of the principal barriers to a functional cure. Blocks to transcriptional elongation play a central role in maintaining the latent state, and several latency reversal strategies focus on the release of positive transcription elongation factor b (P-TEFb) from sequestration by negative regulatory complexes, such as the 7SK complex and BRD4. Another major cellular reservoir of P-TEFb is in Super Elongation Complexes (SECs), which play broad regulatory roles in host gene expression. Still, it is unknown if the release of P-TEFb from SECs is a viable latency reversal strategy. Here, we demonstrate that the SEC is not required for HIV-1 replication in primary CD4+ T cells and that a small molecular inhibitor of the P-TEFb/SEC interaction (termed KL-2) increases viral transcription. KL-2 acts synergistically with other latency reversing agents (LRAs) to reactivate viral transcription in several cell line models of latency in a manner that is, at least in part, dependent on the viral Tat protein. Finally, we demonstrate that KL-2 enhances viral reactivation in peripheral blood mononuclear cells (PBMCs) from people living with HIV (PLWH) on suppressive ART, most notably in combination with inhibitor of apoptosis protein antagonists (IAPi). Taken together, these results suggest that the release of P-TEFb from cellular SECs may be a novel route for HIV-1 latency reactivation.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202235","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}

引用次数: 0

The unique Legionella longbeachae capsule favors intracellular replication and immune evasion 独特的长须鲸军团菌胶囊有利于细胞内复制和免疫逃避

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2024-09-11 DOI: 10.1371/journal.ppat.1012534

Silke Schmidt, Sonia Mondino, Laura Gomez-Valero, Pedro Escoll, Danielle P. A. Mascarenhas, Augusto Gonçalves, Pedro H. M. Camara, Francisco J. Garcia Rodriguez, Christophe Rusniok, Martin Sachse, Maryse Moya-Nilges, Thierry Fontaine, Dario S. Zamboni, Carmen Buchrieser

{"title":"The unique Legionella longbeachae capsule favors intracellular replication and immune evasion","authors":"Silke Schmidt, Sonia Mondino, Laura Gomez-Valero, Pedro Escoll, Danielle P. A. Mascarenhas, Augusto Gonçalves, Pedro H. M. Camara, Francisco J. Garcia Rodriguez, Christophe Rusniok, Martin Sachse, Maryse Moya-Nilges, Thierry Fontaine, Dario S. Zamboni, Carmen Buchrieser","doi":"10.1371/journal.ppat.1012534","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012534","url":null,"abstract":"Legionella longbeachae and Legionella pneumophila are the most common causative agents of Legionnaires’ disease. While the clinical manifestations caused by both species are similar, species-specific differences exist in environmental niches, disease epidemiology, and genomic content. One such difference is the presence of a genomic locus predicted to encode a capsule. Here, we show that L. longbeachae indeed expresses a capsule in post-exponential growth phase as evidenced by electron microscopy analyses, and that capsule expression is abrogated when deleting a capsule transporter gene. Capsule purification and its analysis via HLPC revealed the presence of a highly anionic polysaccharide that is absent in the capsule mutant. The capsule is important for replication and virulence in vivo in a mouse model of infection and in the natural host Acanthamoeba castellanii. It has anti-phagocytic function when encountering innate immune cells such as human macrophages and it is involved in the low cytokine responses in mice and in human monocyte derived macrophages, thus dampening the innate immune response. Thus, the here characterized L. longbeachae capsule is a novel virulence factor, unique among the known Legionella species, which may aid L. longbeachae to survive in its specific niches and which partly confers L. longbeachae its unique infection characteristics.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202234","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}

引用次数: 0

NEDD4 family ubiquitin ligase AIP4 interacts with Alix to enable HBV naked capsid egress in an Alix ubiquitination-independent manner NEDD4 家族泛素连接酶 AIP4 与 Alix 相互作用，以不依赖于 Alix 泛素化的方式使 HBV 裸盖蛋白外排

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2024-09-11 DOI: 10.1371/journal.ppat.1012485

Sheng Shen, Dawei Cai, Hongyan Liang, Ge Zeng, Wendong Liu, Ran Yan, Xiaoyang Yu, Hu Zhang, Shi Liu, Wanying Li, Rui Deng, Xingyu Lu, Yuanjie Liu, Jian Sun, Haitao Guo

{"title":"NEDD4 family ubiquitin ligase AIP4 interacts with Alix to enable HBV naked capsid egress in an Alix ubiquitination-independent manner","authors":"Sheng Shen, Dawei Cai, Hongyan Liang, Ge Zeng, Wendong Liu, Ran Yan, Xiaoyang Yu, Hu Zhang, Shi Liu, Wanying Li, Rui Deng, Xingyu Lu, Yuanjie Liu, Jian Sun, Haitao Guo","doi":"10.1371/journal.ppat.1012485","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012485","url":null,"abstract":"Hepatitis B virus (HBV) exploits the endosomal sorting complexes required for transport (ESCRT)/multivesicular body (MVB) pathway for virion budding. In addition to enveloped virions, HBV-replicating cells nonlytically release non-enveloped (naked) capsids independent of the integral ESCRT machinery, but the exact secretory mechanism remains elusive. Here, we provide more detailed information about the existence and characteristics of naked capsid, as well as the viral and host regulations of naked capsid egress. HBV capsid/core protein has two highly conserved Lysine residues (K7/K96) that potentially undergo various types of posttranslational modifications for subsequent biological events. Mutagenesis study revealed that the K96 residue is critical for naked capsid egress, and the intracellular egress-competent capsids are associated with ubiquitinated host proteins. Consistent with a previous report, the ESCRT-III-binding protein Alix and its Bro1 domain are required for naked capsid secretion through binding to intracellular capsid, and we further found that the ubiquitinated Alix binds to wild type capsid but not K96R mutant. Moreover, screening of NEDD4 E3 ubiquitin ligase family members revealed that AIP4 stimulates the release of naked capsid, which relies on AIP4 protein integrity and E3 ligase activity. We further demonstrated that AIP4 interacts with Alix and promotes its ubiquitination, and AIP4 is essential for Alix-mediated naked capsid secretion. However, the Bro1 domain of Alix is non-ubiquitinated, indicating that Alix ubiquitination is not absolutely required for AIP4-induced naked capsid secretion. Taken together, our study sheds new light on the mechanism of HBV naked capsid egress in viral life cycle.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202296","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}

引用次数: 0

Prion diseases disrupt glutamate/glutamine metabolism in skeletal muscle 朊病毒疾病会破坏骨骼肌中谷氨酸/谷氨酰胺的新陈代谢

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2024-09-11 DOI: 10.1371/journal.ppat.1012552

Davide Caredio, Maruša Koderman, Karl J. Frontzek, Silvia Sorce, Mario Nuvolone, Juliane Bremer, Giovanni Mariutti, Petra Schwarz, Lidia Madrigal, Marija Mitrovic, Stefano Sellitto, Nathalie Streichenberger, Claudia Scheckel, Adriano Aguzzi

{"title":"Prion diseases disrupt glutamate/glutamine metabolism in skeletal muscle","authors":"Davide Caredio, Maruša Koderman, Karl J. Frontzek, Silvia Sorce, Mario Nuvolone, Juliane Bremer, Giovanni Mariutti, Petra Schwarz, Lidia Madrigal, Marija Mitrovic, Stefano Sellitto, Nathalie Streichenberger, Claudia Scheckel, Adriano Aguzzi","doi":"10.1371/journal.ppat.1012552","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012552","url":null,"abstract":"In prion diseases (PrDs), aggregates of misfolded prion protein (PrPSc) accumulate not only in the brain but also in extraneural organs. This raises the question whether prion-specific pathologies arise also extraneurally. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected gene-expression changes in all three organs, with skeletal muscle showing the most consistent alterations. The glutamate-ammonia ligase (GLUL) gene exhibited uniform upregulation in skeletal muscles of mice infected with three distinct scrapie prion strains (RML, ME7, and 22L) and in victims of human sporadic Creutzfeldt-Jakob disease. GLUL dysregulation was accompanied by changes in glutamate/glutamine metabolism, leading to reduced glutamate levels in skeletal muscle. None of these changes were observed in skeletal muscle of humans with amyotrophic lateral sclerosis, Alzheimer’s disease, or dementia with Lewy bodies, suggesting that they are specific to prion diseases. These findings reveal an unexpected metabolic dimension of prion infections and point to a potential role for GLUL dysregulation in the glutamate/glutamine metabolism in prion-affected skeletal muscle.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202236","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}

引用次数: 0

A comprehensive study of SARS-CoV-2 mfigain protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system 对在基于 VSV 的系统中筛选出的 SARS-CoV-2 mfigain 蛋白酶 (Mpro) 抑制剂抗性突变体的全面研究

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2024-09-11 DOI: 10.1371/journal.ppat.1012522

Francesco Costacurta, Andrea Dodaro, David Bante, Helge Schöppe, Ju-Yi Peng, Bernhard Sprenger, Xi He, Seyed Arad Moghadasi, Lisa Maria Egger, Jakob Fleischmann, Matteo Pavan, Davide Bassani, Silvia Menin, Stefanie Rauch, Laura Krismer, Anna Sauerwein, Anne Heberle, Toni Rabensteiner, Joses Ho, Reuben S. Harris, Eduard Stefan, Rainer Schneider, Theresia Dunzendorfer-Matt, Andreas Naschberger, Dai Wang, Teresa Kaserer, Stefano Moro, Dorothee von Laer, Emmanuel Heilmann

{"title":"A comprehensive study of SARS-CoV-2 mfigain protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system","authors":"Francesco Costacurta, Andrea Dodaro, David Bante, Helge Schöppe, Ju-Yi Peng, Bernhard Sprenger, Xi He, Seyed Arad Moghadasi, Lisa Maria Egger, Jakob Fleischmann, Matteo Pavan, Davide Bassani, Silvia Menin, Stefanie Rauch, Laura Krismer, Anna Sauerwein, Anne Heberle, Toni Rabensteiner, Joses Ho, Reuben S. Harris, Eduard Stefan, Rainer Schneider, Theresia Dunzendorfer-Matt, Andreas Naschberger, Dai Wang, Teresa Kaserer, Stefano Moro, Dorothee von Laer, Emmanuel Heilmann","doi":"10.1371/journal.ppat.1012522","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012522","url":null,"abstract":"Nirmatrelvir was the first protease inhibitor specifically developed against the SARS-CoV-2 main protease (3CLpro/Mpro) and licensed for clinical use. As SARS-CoV-2 continues to spread, variants resistant to nirmatrelvir and other currently available treatments are likely to arise. This study aimed to identify and characterize mutations that confer resistance to nirmatrelvir. To safely generate Mpro resistance mutations, we passaged a previously developed, chimeric vesicular stomatitis virus (VSV-Mpro) with increasing, yet suboptimal concentrations of nirmatrelvir. Using Wuhan-1 and Omicron Mpro variants, we selected a large set of mutants. Some mutations are frequently present in GISAID, suggesting their relevance in SARS-CoV-2. The resistance phenotype of a subset of mutations was characterized against clinically available protease inhibitors (nirmatrelvir and ensitrelvir) with cell-based, biochemical and SARS-CoV-2 replicon assays. Moreover, we showed the putative molecular mechanism of resistance based on in silico molecular modelling. These findings have implications on the development of future generation Mpro inhibitors, will help to understand SARS-CoV-2 protease inhibitor resistance mechanisms and show the relevance of specific mutations, thereby informing treatment decisions.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202233","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}

引用次数: 0