PLoS Pathogens最新文献_第4页

Noncanonical Rab9a action supports retromer-mediated endosomal exit of human papillomavirus during virus entry. 非经典Rab9a作用支持逆转录酶介导的人乳头瘤病毒在病毒进入过程中的内体退出。

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2023-09-13 eCollection Date: 2023-09-01 DOI: 10.1371/journal.ppat.1011648

Jeongjoon Choi, Daniel DiMaio

{"title":"Noncanonical Rab9a action supports retromer-mediated endosomal exit of human papillomavirus during virus entry.","authors":"Jeongjoon Choi, Daniel DiMaio","doi":"10.1371/journal.ppat.1011648","DOIUrl":"10.1371/journal.ppat.1011648","url":null,"abstract":"Rab GTPases play key roles in controlling intracellular vesicular transport. GTP-bound Rab proteins support vesicle trafficking. Here, we report that, unlike cellular protein cargos, retromer-mediated delivery of human papillomaviruses (HPV) into the retrograde transport pathway during virus entry is inhibited by Rab9a in its GTP-bound form. Knockdown of Rab9a inhibits HPV entry by modulating the HPV-retromer interaction and impairing retromer-mediated endosome-to-Golgi transport of the incoming virus, resulting in the accumulation of HPV in the endosome. Rab9a is in proximity to HPV as early as 3.5 h post-infection, prior to the Rab7-HPV interaction, and HPV displays increased association with retromer in Rab9a knockdown cells, even in the presence of dominant negative Rab7. Thus, Rab9a can regulate HPV-retromer association independently of Rab7. Surprisingly, excess GTP-Rab9a impairs HPV entry, whereas excess GDP-Rab9a reduces association between L2 and Rab9a and stimulates entry. These findings reveal that HPV and cellular proteins utilize the Rab9a host trafficking machinery in distinct ways during intracellular trafficking.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"19 9","pages":"e1011648"},"PeriodicalIF":6.7,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10597248","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}

引用次数: 0

Adenovirus protein VII binds the A-box of HMGB1 to repress interferon responses. 腺病毒蛋白VII与HMGB1的A-box结合以抑制干扰素反应。

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2023-09-13 eCollection Date: 2023-09-01 DOI: 10.1371/journal.ppat.1011633

Edward A Arnold, Robin J Kaai, Katie Leung, Mia R Brinkley, Laurel E Kelnhofer-Millevolte, Monica S Guo, Daphne C Avgousti

{"title":"Adenovirus protein VII binds the A-box of HMGB1 to repress interferon responses.","authors":"Edward A Arnold, Robin J Kaai, Katie Leung, Mia R Brinkley, Laurel E Kelnhofer-Millevolte, Monica S Guo, Daphne C Avgousti","doi":"10.1371/journal.ppat.1011633","DOIUrl":"10.1371/journal.ppat.1011633","url":null,"abstract":"Viruses hijack host proteins to promote infection and dampen host defenses. Adenovirus encodes the multifunctional protein VII that serves both to compact viral genomes inside the virion and disrupt host chromatin. Protein VII binds the abundant nuclear protein high mobility group box 1 (HMGB1) and sequesters HMGB1 in chromatin. HMGB1 is an abundant host nuclear protein that can also be released from infected cells as an alarmin to amplify inflammatory responses. By sequestering HMGB1, protein VII prevents its release, thus inhibiting downstream inflammatory signaling. However, the consequences of this chromatin sequestration on host transcription are unknown. Here, we employ bacterial two-hybrid interaction assays and human cell culture to interrogate the mechanism of the protein VII-HMGB1 interaction. HMGB1 contains two DNA binding domains, the A- and B-boxes, that bend DNA to promote transcription factor binding while the C-terminal tail regulates this interaction. We demonstrate that protein VII interacts directly with the A-box of HMGB1, an interaction that is inhibited by the HMGB1 C-terminal tail. By cellular fractionation, we show that protein VII renders A-box containing constructs insoluble, thereby acting to prevent their release from cells. This sequestration is not dependent on HMGB1's ability to bind DNA but does require post-translational modifications on protein VII. Importantly, we demonstrate that protein VII inhibits expression of interferon β, in an HMGB1-dependent manner, but does not affect transcription of downstream interferon-stimulated genes. Together, our results demonstrate that protein VII specifically harnesses HMGB1 through its A-box domain to depress the innate immune response and promote infection.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"19 9","pages":"e1011633"},"PeriodicalIF":6.7,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10230411","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}

引用次数: 0

Adaptive evolution in virulence effectors of the rice blast fungus Pyricularia oryzae. 稻瘟病菌稻瘟病菌毒力效应子的适应性进化。

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2023-09-11 eCollection Date: 2023-09-01 DOI: 10.1371/journal.ppat.1011294

Marie Le Naour-Vernet, Florian Charriat, Jérôme Gracy, Sandrine Cros-Arteil, Sébastien Ravel, Florian Veillet, Isabelle Meusnier, André Padilla, Thomas Kroj, Stella Cesari, Pierre Gladieux

{"title":"Adaptive evolution in virulence effectors of the rice blast fungus Pyricularia oryzae.","authors":"Marie Le Naour-Vernet, Florian Charriat, Jérôme Gracy, Sandrine Cros-Arteil, Sébastien Ravel, Florian Veillet, Isabelle Meusnier, André Padilla, Thomas Kroj, Stella Cesari, Pierre Gladieux","doi":"10.1371/journal.ppat.1011294","DOIUrl":"10.1371/journal.ppat.1011294","url":null,"abstract":"Plant pathogens secrete proteins called effectors that target host cellular processes to promote disease. Recently, structural genomics has identified several families of fungal effectors that share a similar three-dimensional structure despite remarkably variable amino-acid sequences and surface properties. To explore the selective forces that underlie the sequence variability of structurally-analogous effectors, we focused on MAX effectors, a structural family of effectors that are major determinants of virulence in the rice blast fungus Pyricularia oryzae. Using structure-informed gene annotation, we identified 58 to 78 MAX effector genes per genome in a set of 120 isolates representing seven host-associated lineages. The expression of MAX effector genes was primarily restricted to the early biotrophic phase of infection and strongly influenced by the host plant. Pangenome analyses of MAX effectors demonstrated extensive presence/absence polymorphism and identified gene loss events possibly involved in host range adaptation. However, gene knock-in experiments did not reveal a strong effect on virulence phenotypes suggesting that other evolutionary mechanisms are the main drivers of MAX effector losses. MAX effectors displayed high levels of standing variation and high rates of non-synonymous substitutions, pointing to widespread positive selection shaping the molecular diversity of MAX effectors. The combination of these analyses with structural data revealed that positive selection acts mostly on residues located in particular structural elements and at specific positions. By providing a comprehensive catalog of amino acid polymorphism, and by identifying the structural determinants of the sequence diversity, our work will inform future studies aimed at elucidating the function and mode of action of MAX effectors.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"19 9","pages":"e1011294"},"PeriodicalIF":6.7,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10513199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10563527","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}

引用次数: 0

A serpin gene from a parasitoid wasp disrupts host immunity and exhibits adaptive alternative splicing. 寄生蜂的serpin基因破坏宿主免疫并表现出适应性选择性剪接。

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2023-09-11 eCollection Date: 2023-09-01 DOI: 10.1371/journal.ppat.1011649

Zhichao Yan, Qi Fang, Jiqiang Song, Lei Yang, Shan Xiao, Jiale Wang, Gongyin Ye

{"title":"A serpin gene from a parasitoid wasp disrupts host immunity and exhibits adaptive alternative splicing.","authors":"Zhichao Yan, Qi Fang, Jiqiang Song, Lei Yang, Shan Xiao, Jiale Wang, Gongyin Ye","doi":"10.1371/journal.ppat.1011649","DOIUrl":"10.1371/journal.ppat.1011649","url":null,"abstract":"Alternative splicing (AS) is a major source of protein diversity in eukaryotes, but less is known about its evolution compared to gene duplication (GD). How AS and GD interact is also largely understudied. By constructing the evolutionary trajectory of the serpin gene PpSerpin-1 (Pteromalus puparum serpin 1) in parasitoids and other insects, we found that both AS and GD jointly contribute to serpin protein diversity. These two processes are negatively correlated and show divergent features in both protein and regulatory sequences. Parasitoid wasps exhibit higher numbers of serpin protein/domains than nonparasitoids, resulting from more GD but less AS in parasitoids. The potential roles of AS and GD in the evolution of parasitoid host-effector genes are discussed. Furthermore, we find that PpSerpin-1 shows an exon expansion of AS compared to other parasitoids, and that several isoforms are involved in the wasp immune response, have been recruited to both wasp venom and larval saliva, and suppress host immunity. Overall, our study provides an example of how a parasitoid serpin gene adapts to parasitism through AS, and sheds light on the differential features of AS and GD in the evolution of insect serpins and their associations with the parasitic life strategy.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"19 9","pages":"e1011649"},"PeriodicalIF":6.7,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10513286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10563526","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}

引用次数: 1

Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation. 肺上皮免疫代谢调节的抗微生物线粒体活性氧诱导。

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2023-09-11 eCollection Date: 2023-09-01 DOI: 10.1371/journal.ppat.1011138

Yongxing Wang, Vikram V Kulkarni, Jezreel Pantaleón García, Miguel M Leiva-Juárez, David L Goldblatt, Fahad Gulraiz, Lisandra Vila Ellis, Jichao Chen, Michael K Longmire, Sri Ramya Donepudi, Philip L Lorenzi, Hao Wang, Lee-Jun Wong, Michael J Tuvim, Scott E Evans

{"title":"Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation.","authors":"Yongxing Wang, Vikram V Kulkarni, Jezreel Pantaleón García, Miguel M Leiva-Juárez, David L Goldblatt, Fahad Gulraiz, Lisandra Vila Ellis, Jichao Chen, Michael K Longmire, Sri Ramya Donepudi, Philip L Lorenzi, Hao Wang, Lee-Jun Wong, Michael J Tuvim, Scott E Evans","doi":"10.1371/journal.ppat.1011138","DOIUrl":"10.1371/journal.ppat.1011138","url":null,"abstract":"Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs' intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"19 9","pages":"e1011138"},"PeriodicalIF":6.7,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10563867","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}

引用次数: 0

Replication cycle timing determines phage sensitivity to a cytidine deaminase toxin/antitoxin bacterial defense system. 复制周期时间决定了噬菌体对胞苷脱氨酶毒素/抗毒素细菌防御系统的敏感性。

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2023-09-08 eCollection Date: 2023-09-01 DOI: 10.1371/journal.ppat.1011195

Brian Y Hsueh, Micah J Ferrell, Ram Sanath-Kumar, Amber M Bedore, Christopher M Waters

{"title":"Replication cycle timing determines phage sensitivity to a cytidine deaminase toxin/antitoxin bacterial defense system.","authors":"Brian Y Hsueh, Micah J Ferrell, Ram Sanath-Kumar, Amber M Bedore, Christopher M Waters","doi":"10.1371/journal.ppat.1011195","DOIUrl":"10.1371/journal.ppat.1011195","url":null,"abstract":"Toxin-antitoxin (TA) systems are ubiquitous two-gene loci that bacteria use to regulate cellular processes such as phage defense. Here, we demonstrate the mechanism by which a novel type III TA system, avcID, is activated and confers resistance to phage infection. The toxin of the system (AvcD) is a deoxycytidylate deaminase that converts deoxycytidines (dC) to dexoyuridines (dU), while the RNA antitoxin (AvcI) inhibits AvcD activity. We have shown that AvcD deaminated dC nucleotides upon phage infection, but the molecular mechanism that activated AvcD was unknown. Here we show that the activation of AvcD arises from phage-induced inhibition of host transcription, leading to degradation of the labile AvcI. AvcD activation and nucleotide depletion not only decreases phage replication but also increases the formation of defective phage virions. Surprisingly, infection of phages such as T7 that are not inhibited by AvcID also lead to AvcI RNA antitoxin degradation and AvcD activation, suggesting that depletion of AvcI is not sufficient to confer protection against some phage. Rather, our results support that phage with a longer replication cycle like T5 are sensitive to AvcID-mediated protection while those with a shorter replication cycle like T7 are resistant.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"19 9","pages":"e1011195"},"PeriodicalIF":6.7,"publicationDate":"2023-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10511110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10227796","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}

引用次数: 0

Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections. 一种与抗微生物肽融合的针对铜绿假单胞菌的抗体的开发：一种预防和治疗细菌感染的新方法。

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2023-09-07 eCollection Date: 2023-09-01 DOI: 10.1371/journal.ppat.1011612

Kenneth Johnson, James C Delaney, Thomas Guillard, Fany Reffuveille, Jennifer Varin-Simon, Kai Li, Andrew Wollacott, Eric Frapy, Surin Mong, Hamid Tissire, Karthik Viswanathan, Faycal Touti, Gregory J Babcock, Zachary Shriver, Bradley L Pentelute, Obadiah Plante, David Skurnik

{"title":"Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections.","authors":"Kenneth Johnson, James C Delaney, Thomas Guillard, Fany Reffuveille, Jennifer Varin-Simon, Kai Li, Andrew Wollacott, Eric Frapy, Surin Mong, Hamid Tissire, Karthik Viswanathan, Faycal Touti, Gregory J Babcock, Zachary Shriver, Bradley L Pentelute, Obadiah Plante, David Skurnik","doi":"10.1371/journal.ppat.1011612","DOIUrl":"10.1371/journal.ppat.1011612","url":null,"abstract":"The increase in emerging drug resistant Gram-negative bacterial infections is a global concern. In addition, there is growing recognition that compromising the microbiota through the use of broad-spectrum antibiotics can impact long term patient outcomes. Therefore, there is the need to develop new bactericidal strategies to combat Gram-negative infections that would address these specific issues. In this study, we report and characterize one such approach, an antibody-drug conjugate (ADC) that combines (i) targeting the surface of a specific pathogenic organism through a monoclonal antibody with (ii) the high killing activity of an antimicrobial peptide. We focused on a major pathogenic Gram-negative bacterium associated with antibacterial resistance: Pseudomonas aeruginosa. To target this organism, we designed an ADC by fusing an antimicrobial peptide to the C-terminal end of the VH and/or VL-chain of a monoclonal antibody, VSX, that targets the core of P. aeruginosa lipopolysaccharide. This ADC demonstrates appropriately minimal levels of toxicity against mammalian cells, rapidly kills P. aeruginosa strains, and protects mice from P. aeruginosa lung infection when administered therapeutically. Furthermore, we found that the ADC was synergistic with several classes of antibiotics. This approach described in this study might result in a broadly useful strategy for targeting specific pathogenic microorganisms without further augmenting antibiotic resistance.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"19 9","pages":"e1011612"},"PeriodicalIF":6.7,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10508631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10652879","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}

引用次数: 2

Lodderomyces elongisporus: An emerging human fungal pathogen. Lodderomyces elogisporus：一种新出现的人类真菌病原体。

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2023-09-07 eCollection Date: 2023-09-01 DOI: 10.1371/journal.ppat.1011613

Yue Wang, Jianping Xu

引用次数: 0

Inhibition of ATM-directed antiviral responses by HIV-1 Vif. HIV-1Vif对ATM导向的抗病毒反应的抑制作用。

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2023-09-05 eCollection Date: 2023-09-01 DOI: 10.1371/journal.ppat.1011634

Hoi Tong Wong, Adeline M Luperchio, Sean Riley, Daniel J Salamango

{"title":"Inhibition of ATM-directed antiviral responses by HIV-1 Vif.","authors":"Hoi Tong Wong, Adeline M Luperchio, Sean Riley, Daniel J Salamango","doi":"10.1371/journal.ppat.1011634","DOIUrl":"10.1371/journal.ppat.1011634","url":null,"abstract":"Emerging evidence indicates that HIV-1 hijacks host DNA damage repair (DDR) pathways to facilitate multiple facets of virus replication. Canonically, HIV-1 engages proviral DDR responses through the accessory protein Vpr, which induces constitutive activation of DDR kinases ATM and ATR. However, in response to prolonged DDR signaling, ATM directly induces pro-inflammatory NF-κB signaling and activates multiple members of the TRIM family of antiviral restriction factors, several of which have been previously implicated in antagonizing retroviral and lentiviral replication. Here, we demonstrate that the HIV-1 accessory protein Vif blocks ATM-directed DNA repair processes, activation of NF-κB signaling responses, and TRIM protein phosphorylation. Vif function in ATM antagonism occurs in clinical isolates and in common HIV-1 Group M subtypes/clades circulating globally. Pharmacologic and functional studies combine to suggest that Vif blocks Vpr-directed activation of ATM but not ATR, signifying that HIV-1 utilizes discrete strategies to fine-tune DDR responses that promote virus replication while simultaneously inhibiting immune activation.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"19 9","pages":"e1011634"},"PeriodicalIF":6.7,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10503699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10336365","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}

引用次数: 0

Evidence for preexisting prion substrain diversity in a biologically cloned prion strain. 生物学克隆朊病毒株中预先存在朊病毒亚基多样性的证据。

IF 6.7 1区医学

PLoS Pathogens Pub Date : 2023-09-05 eCollection Date: 2023-09-01 DOI: 10.1371/journal.ppat.1011632

Tess Gunnels, Ronald A Shikiya, Taylor C York, Alyssa J Block, Jason C Bartz

{"title":"Evidence for preexisting prion substrain diversity in a biologically cloned prion strain.","authors":"Tess Gunnels, Ronald A Shikiya, Taylor C York, Alyssa J Block, Jason C Bartz","doi":"10.1371/journal.ppat.1011632","DOIUrl":"10.1371/journal.ppat.1011632","url":null,"abstract":"Prion diseases are a group of inevitably fatal neurodegenerative disorders affecting numerous mammalian species, including Sapiens. Prions are composed of PrPSc, the disease specific conformation of the host encoded prion protein. Prion strains are operationally defined as a heritable phenotype of disease under controlled transmission conditions. Treatment of rodents with anti-prion drugs results in the emergence of drug-resistant prion strains and suggest that prion strains are comprised of a dominant strain and substrains. While much experimental evidence is consistent with this hypothesis, direct observation of substrains has not been observed. Here we show that replication of the dominant strain is required for suppression of a substrain. Based on this observation we reasoned that selective reduction of the dominant strain may allow for emergence of substrains. Using a combination of biochemical methods to selectively reduce drowsy (DY) PrPSc from biologically-cloned DY transmissible mink encephalopathy (TME)-infected brain resulted in the emergence of strains with different properties than DY TME. The selection methods did not occur during prion formation, suggesting the substrains identified preexisted in the DY TME-infected brain. We show that DY TME is biologically stable, even under conditions of serial passage at high titer that can lead to strain breakdown. Substrains therefore can exist under conditions where the dominant strain does not allow for substrain emergence suggesting that substrains are a common feature of prions. This observation has mechanistic implications for prion strain evolution, drug resistance and interspecies transmission.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"19 9","pages":"e1011632"},"PeriodicalIF":6.7,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10503715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10336364","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}

引用次数: 0