PLoS Pathogens最新文献

{"title":"Dynamin independent endocytosis is an alternative cell entry mechanism for multiple animal viruses.","authors":"Ravi Ojha, Anmin Jiang, Elina Mäntylä, Tania Quirin, Naphak Modhira, Robert Witte, Arnaud Gaudin, Lisa De Zanetti, Rachel Sarah Gormal, Maija Vihinen-Ranta, Jason Mercer, Maarit Suomalainen, Urs F Greber, Yohei Yamauchi, Pierre-Yves Lozach, Ari Helenius, Olli Vapalahti, Paul Young, Daniel Watterson, Frédéric A Meunier, Merja Joensuu, Giuseppe Balistreri","doi":"10.1371/journal.ppat.1012690","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012690","url":null,"abstract":"<p><p>Mammalian receptor-mediated endocytosis (RME) often involves at least one of three isoforms of the large GTPase dynamin (Dyn). Dyn pinches-off vesicles at the plasma membrane and mediates uptake of many viruses, although some viruses directly penetrate the plasma membrane. RME is classically interrogated by genetic and pharmacological interference, but this has been hampered by undesired effects. Here we studied virus entry in conditional genetic knock-out (KO) mouse embryonic fibroblasts lacking expression of all three dynamin isoforms (Dyn-KO-MEFs). The small canine parvovirus known to use a single receptor, transferrin receptor, strictly depended on dynamin. Larger viruses or viruses known to use multiple receptors, including alphaviruses, influenza, vesicular stomatitis, bunya, adeno, vaccinia, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and rhinoviruses infected Dyn-KO-MEFs, albeit at higher dosage than wild-type MEFs. In absence of the transmembrane protease serine subtype 2 (TMPRSS2), which normally activates the SARS-CoV-2 spike protein for plasma membrane fusion, SARS-CoV-2 infected angiotensin-converting enzyme 2 (ACE2)-expressing MEFs predominantly through dynamin- and actin-dependent endocytosis. In presence of TMPRSS2 the ancestral Wuhan-strain bypassed both dynamin-dependent and -independent endocytosis, and was less sensitive to endosome maturation inhibitors than the Omicron B1 and XBB variants, supporting the notion that the Omicron variants do not efficiently use TMPRSS2. Collectively, our study suggests that dynamin function at endocytic pits can be essential for infection with single-receptor viruses, while it is not essential but increases uptake and infection efficiency of multi-receptor viruses that otherwise rely on a functional actin network for infection.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012690"},"PeriodicalIF":5.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629689","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":"Single-cell transcriptomics unveils skin cell specific antifungal immune responses and IL-1Ra- IL-1R immune evasion strategies of emerging fungal pathogen Candida auris.","authors":"Abishek Balakumar, Diprasom Das, Abhishek Datta, Abtar Mishra, Garrett Bryak, Shrihari M Ganesh, Mihai G Netea, Vinod Kumar, Michail S Lionakis, Devender Arora, Jyothi Thimmapuram, Shankar Thangamani","doi":"10.1371/journal.ppat.1012699","DOIUrl":"10.1371/journal.ppat.1012699","url":null,"abstract":"<p><p>Candida auris is an emerging multidrug-resistant fungal pathogen that preferentially colonizes and persists in skin tissue, yet the host immune factors that regulate the skin colonization of C. auris in vivo are unknown. In this study, we employed unbiased single-cell transcriptomics of murine skin infected with C. auris to understand the cell type-specific immune response to C. auris. C. auris skin infection results in the accumulation of immune cells such as neutrophils, inflammatory monocytes, macrophages, dendritic cells, T cells, and NK cells at the site of infection. We identified fibroblasts as a major non-immune cell accumulated in the C. auris infected skin tissue. The comprehensive single-cell profiling revealed the transcriptomic signatures in cytokines, chemokines, host receptors (TLRs, C-type lectin receptors, NOD receptors), antimicrobial peptides, and immune signaling pathways in individual immune and non-immune cells during C. auris skin infection. Our analysis revealed that C. auris infection upregulates the expression of the IL-1RN gene (encoding IL-1R antagonist protein) in different cell types. We found IL-1Ra produced by macrophages during C. auris skin infection decreases the killing activity of neutrophils. Furthermore, C. auris uses a unique cell wall mannan outer layer to evade IL-1R-signaling mediated host defense. Collectively, our single-cell RNA seq profiling identified the transcriptomic signatures in immune and non-immune cells during C. auris skin infection. Our results demonstrate the IL-1Ra and IL-1R-mediated immune evasion mechanisms employed by C. auris to persist in the skin. These results enhance our understanding of host defense and immune evasion mechanisms during C. auris skin infection and identify potential targets for novel antifungal therapeutics.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012699"},"PeriodicalIF":5.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630630","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":"ACE2-independent sarbecovirus cell entry can be supported by TMPRSS2-related enzymes and can reduce sensitivity to antibody-mediated neutralization.","authors":"Lu Zhang, Hsiu-Hsin Cheng, Nadine Krüger, Bojan Hörnich, Luise Graichen, Alexander S Hahn, Sebastian R Schulz, Hans-Martin Jäck, Metodi V Stankov, Georg M N Behrens, Marcel A Müller, Christian Drosten, Onnen Mörer, Martin Sebastian Winkler, ZhaoHui Qian, Stefan Pöhlmann, Markus Hoffmann","doi":"10.1371/journal.ppat.1012653","DOIUrl":"10.1371/journal.ppat.1012653","url":null,"abstract":"<p><p>The COVID-19 pandemic, caused by SARS-CoV-2, demonstrated that zoonotic transmission of animal sarbecoviruses threatens human health but the determinants of transmission are incompletely understood. Here, we show that most spike (S) proteins of horseshoe bat and Malayan pangolin sarbecoviruses employ ACE2 for entry, with human and raccoon dog ACE2 exhibiting broad receptor activity. The insertion of a multibasic cleavage site into the S proteins increased entry into human lung cells driven by most S proteins tested, suggesting that acquisition of a multibasic cleavage site might increase infectivity of diverse animal sarbecoviruses for the human respiratory tract. In contrast, two bat sarbecovirus S proteins drove cell entry in an ACE2-independent, trypsin-dependent fashion and several ACE2-dependent S proteins could switch to the ACE2-independent entry pathway when exposed to trypsin. Several TMPRSS2-related cellular proteases but not the insertion of a multibasic cleavage site into the S protein allowed for ACE2-independent entry in the absence of trypsin and may support viral spread in the respiratory tract. Finally, the pan-sarbecovirus antibody S2H97 enhanced cell entry driven by two S proteins and this effect was reversed by trypsin while trypsin protected entry driven by a third S protein from neutralization by S2H97. Similarly, plasma from quadruple vaccinated individuals neutralized entry driven by all S proteins studied, and availability of the ACE2-independent, trypsin-dependent pathway reduced neutralization sensitivity. In sum, our study reports a pathway for entry into human cells that is ACE2-independent, can be supported by TMPRSS2-related proteases and may be associated with antibody evasion.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012653"},"PeriodicalIF":5.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631147","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":"EhRacM differentially regulates macropinocytosis and motility in the enteric protozoan parasite Entamoeba histolytica.","authors":"Misato Shimoyama, Kumiko Nakada-Tsukui, Tomoyoshi Nozaki","doi":"10.1371/journal.ppat.1012364","DOIUrl":"10.1371/journal.ppat.1012364","url":null,"abstract":"<p><p>Macropinocytosis is an evolutionarily conserved endocytic process that plays a vital role in internalizing extracellular fluids and particles in cells. This non-selective endocytic pathway is crucial for various physiological functions such as nutrient uptake, sensing, signaling, antigen presentation, and cell migration. While macropinocytosis has been extensively studied in macrophages and cancer cells, the molecular mechanisms of macropinocytosis in pathogens are less understood. It has been known that Entamoeba histolytica, the causative agent of amebiasis, exploits macropinocytosis for survival and pathogenesis. Since macropinocytosis is initiated by actin polymerization, leading to the formation of membrane ruffles and the subsequent trapping of solutes in macropinosomes, actin cytoskeleton regulation is crucial. Thus, this study focuses on unraveling the role of well-conserved actin cytoskeleton regulators, Rho small GTPase family proteins, in macropinocytosis in E. histolytica. Through gene silencing of highly transcribed Ehrho/Ehrac genes and following flow cytometry analysis, we identified that silencing EhracM enhances dextran macropinocytosis and affects cellular migration persistence. Live imaging and interactome analysis unveiled the cytosolic and vesicular localization of EhRacM, along with its interaction with signaling and membrane traffic-related proteins, shedding light on EhRacM's multiple roles. Our findings provide insights into the specific regulatory mechanisms of macropinocytosis among endocytic pathways in E. histolytica, highlighting the significance of EhRacM in both macropinocytosis and cellular migration.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012364"},"PeriodicalIF":5.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629832","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":"Anchorage of bacterial effector at plasma membrane via selective phosphatidic acid binding to modulate host cell signaling.","authors":"Meng Wang, Qixiao Guan, Chunyan Wang, Lyubin Hu, Xueyan Hu, Menglin Xu, Yuhao Cai, Haoran Zhang, Qing Cao, Huiming Sheng, Xiaohui Wei, Jane E Koehler, Hongjing Dou, Ruo-Xu Gu, Congli Yuan","doi":"10.1371/journal.ppat.1012694","DOIUrl":"10.1371/journal.ppat.1012694","url":null,"abstract":"<p><p>Binding phospholipid is a simple, yet flexible, strategy for anchorage of bacterial effectors at cell membrane to manipulate host signaling responses. Phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-biphosphate are the only two phospholipid species known to direct bacterial effectors to establish inner leaflet localization at the plasma membrane. Here, selectivity of phosphatidic acid (PA) by bacterial effectors for the plasma membrane anchorage and its molecular entity was identified. C-terminal BID domain of Bartonella T4SS effectors (Beps) directed the plasma membrane localization of Beps in host cells through binding with PA. A hydrophobic segment of the 'HOOK' subdomain from BID is inserted into the bilayer to enhance the interaction of positively charged residues with the lipid headgroups. Mutations of a conserved arginine facilitating the electrostatic interaction, a conserved glycine maintaining the stability of the PA binding groove, and hydrophobic residues determining membrane insertion, prevented the anchorage of Beps at the plasma membrane. Disassociation from plasma membrane to cytosol attenuated the BepC capacity to induce stress fiber formation and cell fragmentation in host cells. The substitution of alanine with aspartic acid at the -1 position preceding the conserved arginine residue hindered BepD anchoring at the plasma membrane, a vital prerequisite for its ability to elicit IL-10 secretion in host macrophages. In conclusion, our findings reveal the PA-binding properties of bacterial effectors to establish plasma membrane localization and will shed light on the intricate mechanisms employed by bacterial effectors within host cells.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012694"},"PeriodicalIF":5.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11556746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631148","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":"Mycoplasma bovis 5'-nucleotidase is a virulence factor conferring mammary fitness in bovine mastitis.","authors":"Aga E Gelgie, Peleg Schneider, Christine Citti, Emilie Dordet-Frisoni, Barbara E Gillespie, Raúl A Almeida, Getahun E Agga, Yaa Serwaah Amoah, Nahum Y Shpigel, Oudessa Kerro Dego, Inna Lysnyansky","doi":"10.1371/journal.ppat.1012628","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012628","url":null,"abstract":"<p><p>Nucleases and 5' nucleotidase (5'-NT) play essential roles in cell biology and are often associated with bacterial virulence. In Mycoplasma spp., which have limited metabolic capacities and rely on nutrient availability, these enzymes are of significant importance for nucleotide salvage. This study explores the potential role of 2 membrane-associated lipoproteins, the major nuclease MnuA and 5'-NT, in Mycoplasma bovis mastitis. Mutants deficient in MnuA (mnuA::Tn) and in 5'-NT (0690::Tn) were identified through genome-wide transposon mutagenesis of M. bovis PG45 type strain and their fitness and virulence were assessed both in vitro, in axenic medium, and in vivo, using murine and cow mastitis models. The mnuA::Tn mutant demonstrated reduced nuclease activity, while 0690::Tn exhibited slow log-phase growth and impaired hydrolase activity towards nucleotides as well as deoxynucleotides (dAMP and dGMP). In comparison to the parent strain, the 0690::Tn mutant displayed markedly reduced fitness, as evidenced by a significant decrease or even absence in post-challenge mycoplasma counts in murine and cow mammary tissues, respectively. Moreover, the 0690::Tn mutant failed to induce mastitis in both experimental models. Conversely, the mnuA::Tn mutant induced inflammation in murine mammary glands, characterized by neutrophil infiltration and increased expression of major inflammatory genes. In cows, the mnuA::Tn was able to cause an increase in somatic cell counts in a manner comparable to the wild type, recruit neutrophils, and induce mastitis. Collectively, these findings provide complementary insights, revealing that disruption of 5'-NT significantly attenuated M. bovis pathogenicity, whereas a MnuA-deficient mutant retained the ability to cause mastitis.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012628"},"PeriodicalIF":5.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630373","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":"TRIM32 inhibits Venezuelan equine encephalitis virus infection by targeting a late step in viral entry.","authors":"Yifan Xie, Jie Cao, Shuyi Gan, Lingdong Xu, Dongjie Zhang, Suhong Qian, Feng Xu, Qiang Ding, John W Schoggins, Wenchun Fan","doi":"10.1371/journal.ppat.1012312","DOIUrl":"10.1371/journal.ppat.1012312","url":null,"abstract":"<p><p>Alphaviruses are mosquito borne RNA viruses that are a reemerging public health threat. Alphaviruses have a broad host range, and can cause diverse disease outcomes like arthritis, and encephalitis. The host ubiquitin proteasome system (UPS) plays critical roles in regulating cellular processes to control the infections with various viruses, including alphaviruses. Previous studies suggest alphaviruses hijack UPS for virus infection, but the molecular mechanisms remain poorly characterized. In addition, whether certain E3 ubiquitin ligases or deubiquitinases act as alphavirus restriction factors remains poorly understood. Here, we employed a cDNA expression screen to identify E3 ubiquitin ligase TRIM32 as a novel intrinsic restriction factor against alphavirus infection, including VEEV-TC83, SINV, and ONNV. Ectopic expression of TRIM32 reduces alphavirus infection, whereas depletion of TRIM32 with CRISPR-Cas9 increases infection. We demonstrate that TRIM32 inhibits alphaviruses through a mechanism that is independent of the TRIM32-STING-IFN axis. Combining reverse genetics and biochemical assays, we found that TRIM32 interferes with genome translation after membrane fusion, prior to replication of the incoming viral genome. Furthermore, our data indicate that the monoubiquitination of TRIM32 is important for its antiviral activity. Notably, we also show two TRIM32 pathogenic mutants R394H and D487N, related to Limb-girdle muscular dystrophy (LGMD), have a loss of antiviral activity against VEEV-TC83. Collectively, these results reveal that TRIM32 acts as a novel intrinsic restriction factor suppressing alphavirus infection and provides insights into the interaction between alphaviruses and the host UPS.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012312"},"PeriodicalIF":5.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11581401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630668","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":"Critical role of Babesia bovis spherical body protein 3 in ridge formation on infected red blood cells.","authors":"Atefeh Fathi, Hassan Hakimi, Miako Sakaguchi, Junya Yamagishi, Shin-Ichiro Kawazu, Masahito Asada","doi":"10.1371/journal.ppat.1012294","DOIUrl":"10.1371/journal.ppat.1012294","url":null,"abstract":"<p><p>Babesia bovis, an apicomplexan intraerythrocytic protozoan parasite, causes serious economic loss to cattle industries around the world. Infection with this parasite leads to accumulation of infected red blood cells (iRBCs) in the brain microvasculature that results in severe clinical complications known as cerebral babesiosis. Throughout its growth within iRBCs, the parasite exports various proteins to the iRBCs that lead to the formation of protrusions known as \"ridges\" on the surface of iRBCs, which serve as sites for cytoadhesion to endothelial cells. Spherical body proteins (SBPs; proteins secreted from spherical bodies, which are organelles specific to Piroplasmida) are exported into iRBCs, and four proteins (SBP1-4) have been reported to date. In this study, we elucidated the function of SBP3 using an inducible gene knockdown (KD) system. Localization of SBP3 was assessed by immunofluorescence assay, and only partial colocalization was detected between SBP3 and SBP4 inside the iRBCs. In contrast, colocalization was observed with VESA-1, which is a major parasite ligand responsible for the cytoadhesion. Immunoelectron microscopy confirmed localization of SBP3 at the ridges. SBP3 KD was performed using the glmS system, and effective KD was confirmed by Western blotting, immunofluorescence assay, and RNA-seq analysis. The SBP3 KD parasites showed severe growth defect suggesting its importance for parasite survival in the iRBCs. VESA-1 on the surface of iRBCs was scarcely detected in SBP3 KD parasites, whereas SBP4 was still detected in the iRBCs. Moreover, abolition of ridges on the iRBCs and reduction of iRBCs cytoadhesion to the bovine brain endothelial cells were observed in SBP3 KD parasites. Immunoprecipitation followed by mass spectrometry analysis detected the host Band 3 multiprotein complex, suggesting an association of SBP3 with iRBC cytoskeleton proteins. Taken together, this study revealed the vital role of SBP3 in ridge formation and its significance in the pathogenesis of cerebral babesiosis.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012294"},"PeriodicalIF":5.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11581398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629740","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":"A model of lymphocryptovirus-associated post-transplant lymphoproliferative disorder in immunosuppressed Mauritian cynomolgus macaques.","authors":"Helen L Wu, Whitney C Weber, Courtney M Waytashek, Carla D Boyle, Jason S Reed, Katherine B Bateman, Hannah K Fisher, Yan Chen, Kimberly Armantrout, Tonya Swanson, Christine Shriver-Munsch, Mina Northrup, Miranda Fischer, Sreya Biswas, John Templon, Angela Panoskaltsis-Mortari, Benjamin J Burwitz, Amanda L Johnson, Lois Colgin, Anne D Lewis, Jeremy V Smedley, Michael K Axthelm, Rebecca Skalsky, Gabrielle Meyers, Richard T Maziarz, Erik Mittra, Melissa Berg, Jeffrey J Stanton, Jonah B Sacha","doi":"10.1371/journal.ppat.1012644","DOIUrl":"10.1371/journal.ppat.1012644","url":null,"abstract":"<p><p>Immunocompromised individuals are at risk for developing lymphocryptovirus-associated lymphoproliferative diseases, such as Epstein Barr virus (EBV)-associated B cell lymphomas and post-transplant lymphoproliferative disorder (PTLD). We previously reported development of cynomolgus lymphocryptovirus (CyLCV)-associated PTLD in Mauritian cynomolgus macaques (MCMs) undergoing hematopoietic stem cell transplantation (HSCT), which mirrored EBV-PTLD in transplant patients. Here, we sought to develop a MCM model of lymphocryptovirus-associated lymphoproliferative disease in immunosuppressed MCMs without HSCT. Five simian immunodeficiency virus (SIV)-infected, CD8α+ cell-depleted MCMs received an infusion of autologous B-lymphoblastoid cells transformed with CyLCV, followed by varying degrees of immunosuppression. Four of five infused macaques developed masses coincident with increasing CyLCV plasma viremia, and necropsies confirmed the presence of multicentric lymphomas, which most commonly manifested in lymph nodes, gastrointestinal tract, adrenal glands, and pancreas. Affected tissues harbored neoplastic lymphocytes double-positive for CD20 and CyLCV EBNA2 antigen, large frequencies of proliferating B cells, and high levels of cell-associated CyLCV DNA. In addition, longitudinal 18F-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) of one MCM successfully detected lymphoproliferative disease in the adrenal glands prior to clinical signs of disease. These data demonstrate successful induction of lymphocryptovirus-associated PTLD-like disease in 4 of 5 MCMs, and thus support the use of MCMs as a preclinical NHP model of EBV-associated lymphoproliferative disease that could be employed to test novel diagnostic and therapeutic modalities.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012644"},"PeriodicalIF":5.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11581395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631146","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":"Super broad and protective nanobodies against Sarbecoviruses including SARS-CoV-1 and the divergent SARS-CoV-2 subvariant KP.3.1.1.","authors":"Haodi Dong, Runhong Zhou, Jing Chen, Jing Wei, Zimeng Wei, Ziqing Yang, Kun Zhu, Yufan Yang, Qianqian Yang, Na Liu, Yuting Chen, Yuhan Wu, Yan Liang, Yige Zeng, Qile Guo, Mingxi Li, Sisi Shan, Han Wang, Mengyue Niu, Isabella Yunfei Zeng, Xuanling Shi, Qi Zhang, Xinquan Wang, Zhiwei Chen, Linqi Zhang","doi":"10.1371/journal.ppat.1012625","DOIUrl":"10.1371/journal.ppat.1012625","url":null,"abstract":"<p><p>The ongoing evolution and immune escape of SARS-CoV-2, alongside the potential threat of SARS-CoV-1 and other sarbecoviruses, underscore the urgent need for effective strategies against their infection and transmission. This study highlights the discovery of nanobodies from immunized alpacas, which demonstrate exceptionally broad and potent neutralizing capabilities against the recently emerged and more divergent SARS-CoV-2 Omicron subvariants including JD.1.1, JN.1, KP.3, KP.3.1.1, as well as SARS-CoV-1 and coronaviruses from bats and pangolins utilizing receptor ACE2. Among these, Tnb04-1 emerges as the most broad and potent, binding to a conserved hydrophobic pocket in the spike's receptor-binding domain, distinct from the ACE2 binding site. This interaction disrupts the formation of a proteinase K-resistant core, crucial for viral-cell fusion. Notably, intranasal administration of Tnb04-1 in Syrian hamsters effectively prevented respiratory infection and transmission of the authentic Omicron XBB.1.5 subvariant. Thus, Thb04-1 holds promise in combating respiratory acquisition and transmission of diverse sarbecoviruses.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012625"},"PeriodicalIF":5.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630611","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}