PLoS Pathogens最新文献

{"title":"Eimeria: Navigating complex intestinal ecosystems.","authors":"Shengjie Weng, Erjie Tian, Meng Gao, Siyu Zhang, Guodong Yang, Bianhua Zhou","doi":"10.1371/journal.ppat.1012689","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012689","url":null,"abstract":"<p><p>Eimeria is an intracellular obligate apicomplexan parasite that parasitizes the intestinal epithelial cells of livestock and poultry, exhibiting strong host and tissue tropism. Parasite-host interactions involve complex networks and vary as the parasites develop in the host. However, understanding the underlying mechanisms remains a challenge. Acknowledging the lack of studies on Eimeria invasion mechanism, we described the possible invasion process through comparative analysis with other apicomplexan parasites and explored the fact that parasite-host interactions serve as a prerequisite for successful recognition, penetration of the intestinal mechanical barrier, and completion of the invasion. Although it is recognized that microbiota can enhance the host immune capacity to resist Eimeria invasion, changes in the microenvironment can, in turn, contribute to Eimeria invasion and may be associated with reduced immune capacity. We also discuss the immune evasion strategies of Eimeria, emphasizing that the host employs sophisticated immune regulatory mechanisms to suppress immune evasion by parasites, thereby sustaining a balanced immune response. This review aims to deepen our understanding of Eimeria-host interactions, providing a theoretical basis for the study of the pathogenicity of Eimeria and the development of novel anticoccidial drugs.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012689"},"PeriodicalIF":5.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693848","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":"SARS-CoV-2 evolution balances conflicting roles of N protein phosphorylation.","authors":"Abdullah M Syed, Alison Ciling, Irene P Chen, Christopher R Carlson, Armin N Adly, Hannah S Martin, Taha Y Taha, Mir M Khalid, Nathan Price, Mehdi Bouhaddou, Manisha R Ummadi, Jack M Moen, Nevan J Krogan, David O Morgan, Melanie Ott, Jennifer A Doudna","doi":"10.1371/journal.ppat.1012741","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012741","url":null,"abstract":"<p><p>All lineages of SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, contain mutations between amino acids 199 and 205 in the nucleocapsid (N) protein that are associated with increased infectivity. The effects of these mutations have been difficult to determine because N protein contributes to both viral replication and viral particle assembly during infection. Here, we used single-cycle infection and virus-like particle assays to show that N protein phosphorylation has opposing effects on viral assembly and genome replication. Ancestral SARS-CoV-2 N protein is densely phosphorylated, leading to higher levels of genome replication but 10-fold lower particle assembly compared to evolved variants with low N protein phosphorylation, such as Delta (N:R203M), Iota (N:S202R), and B.1.2 (N:P199L). A new open reading frame encoding a truncated N protein called N*, which occurs in the B.1.1 lineage and subsequent lineages of the Alpha, Gamma, and Omicron variants, supports high levels of both assembly and replication. Our findings help explain the enhanced fitness of viral variants of concern and a potential avenue for continued viral selection.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012741"},"PeriodicalIF":5.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689321","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":"Massive entry of BK Polyomavirus induces transient cytoplasmic vacuolization of human renal proximal tubule epithelial cells.","authors":"Elias Myrvoll Lorentzen, Stian Henriksen, Christine Hanssen Rinaldo","doi":"10.1371/journal.ppat.1012681","DOIUrl":"10.1371/journal.ppat.1012681","url":null,"abstract":"<p><p>BK polyomavirus (BKPyV) is a ubiquitous human virus that establishes a persistent infection in renal tubular epithelial cells and mainly causes disease in kidney transplant recipients. The closely related simian polyomavirus SV40 is known to cause cytoplasmic vacuolization in simian kidney cells, possibly increasing progeny release and cell death. This study aimed to determine whether BKPyV causes cytoplasmic vacuolization in primary human renal proximal tubule epithelial cells (RPTECs) and to investigate its potential role in the replication cycle. Using a large infectious dose (MOI 100-1000), a fraction of RPTECs (10-72%) showed early-wave vacuolization from 3 hours post-infection (hpi), which was mainly reversed by 36 hpi. Independent of the infectious dose, late-wave vacuolization occurred around the timepoint of progeny release. BKPyV receptor binding and internalization were required, as neuraminidase pretreatment and preincubation or treatment with a BKPyV-specific neutralizing antibody prevented early or late-occurring vacuolization. Microscopy revealed that the vacuoles were enlarged acidic endo-/lysosomal structures (dextran, EEA1, Rab5, Rab7, LAMP1, and/or Lysoview positive) that contained membrane-bound BKPyV. Time-lapse microscopy and quantitative PCR revealed that cell death and progeny release preceded late-wave vacuolization, mainly affecting cells directly neighboring the lysed cells. Thus, vacuolization had little impact on cell death or progeny release. Addition of the V-ATPase inhibitor Bafilomycin A1 at 0 hpi blocked vacuolization and BKPyV replication, but addition at 2 hpi only blocked vacuolization, suggesting that continuous endosomal acidification and maturation is needed for vacuole formation, but not for BKPyV replication. Our study shows that a massive uptake of BKPyV in RPTECs induces transient enlargement of endo-/lysosomes and is an early event in the viral replication cycle. Vacuolization gives no clear benefit for BKPyV and is possibly the result of a transiently overloaded endocytic pathway. Focal vacuolization around lysed cells suggests that the spread of BKPyV is preferably local.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012681"},"PeriodicalIF":5.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11581322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689320","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":"Diclofenac sensitizes multi-drug resistant Acinetobacter baumannii to colistin.","authors":"Fabiana Bisaro, Clay D Jackson-Litteken, Jenna C McGuffey, Anna J Hooppaw, Sophie Bodrog, Leila Jebeli, Manon Janet-Maitre, Juan C Ortiz-Marquez, Tim van Opijnen, Nichollas E Scott, Gisela Di Venanzio, Mario F Feldman","doi":"10.1371/journal.ppat.1012705","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012705","url":null,"abstract":"<p><p>Acinetobacter baumannii causes life-threatening infections that are becoming difficult to treat due to increasing rates of multi-drug resistance (MDR) among clinical isolates. This has led the World Health Organization and the CDC to categorize MDR A. baumannii as a top priority for the research and development of new antibiotics. Colistin is the last-resort antibiotic to treat carbapenem-resistant A. baumannii. Not surprisingly, reintroduction of colistin has resulted in the emergence of colistin-resistant strains. Diclofenac is a nonsteroidal anti-inflammatory drug used to treat pain and inflammation associated with arthritis. In this work, we show that diclofenac sensitizes colistin-resistant A. baumannii clinical strains to colistin, in vitro and in a murine model of pneumonia. Diclofenac also reduced the colistin minimal inhibitory concentration (MIC) of Klebsiella pneumoniae and Pseudomonas aeruginosa isolates. Transcriptomic and proteomic analyses revealed an upregulation of oxidative stress-related genes and downregulation of type IV pili induced by the combination treatment. Notably, the concentrations of colistin and diclofenac effective in the murine model were substantially lower than those determined in vitro, implying a stronger synergistic effect in vivo compared to in vitro. A pilA mutant strain, lacking the primary component of the type IV pili, became sensitive to colistin in the absence of diclofenac. This suggest that the downregulation of type IV pili is key for the synergistic activity of these drugs in vivo and indicates that colistin and diclofenac exert an anti-virulence effect. Together, these results suggest that the diclofenac can be repurposed with colistin to treat MDR A. baumannii.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012705"},"PeriodicalIF":5.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689170","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":"Bipolaris or Curvularia? Resolving the spicy issue of how clinical isolates should be reported.","authors":"Sarah E Kidd, Lars F Westblade","doi":"10.1371/journal.ppat.1012678","DOIUrl":"10.1371/journal.ppat.1012678","url":null,"abstract":"","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012678"},"PeriodicalIF":5.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11578450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683264","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":"Enterovirus A71 and coxsackievirus A6 circulation in England, UK, 2006-2017: A mathematical modelling study using cross-sectional seroprevalence data.","authors":"Everlyn Kamau, Ben Lambert, David J Allen, Cristina Celma, Stuart Beard, Heli Harvala, Peter Simmonds, Nicholas C Grassly, Margarita Pons-Salort","doi":"10.1371/journal.ppat.1012703","DOIUrl":"10.1371/journal.ppat.1012703","url":null,"abstract":"<p><p>Enterovirus A71 (EV-A71) and coxsackievirus A6 (CVA6) primarily cause hand, foot and mouth disease and have emerged to cause potential fatal neurological and systemic manifestations. However, limited surveillance data collected through passive surveillance systems hampers characterization of their epidemiological dynamics. We fit a series of catalytic models to age-stratified seroprevalence data for EV-A71 and CVA6 collected in England at three time points (2006, 2011 and 2017) to estimate the force of infection (FOI) over time and assess possible changes in transmission. For both serotypes, model comparison does not support the occurrence of important changes in transmission over the study period, and we find that a declining risk of infection with age and / or seroreversion are needed to explain the seroprevalence data. Furthermore, we provide evidence that the increased number of reports of CVA6 during 2006-2017 is unlikely to be explained by changes in surveillance. Therefore, we hypothesize that the increased number of CVA6 cases observed since 2011 must be explained by increased virus pathogenicity. Further studies of seroprevalence data from other countries would allow to confirm this. Our results underscore the value of seroprevalence data to unravel changes in the circulation dynamics of pathogens with weak surveillance systems and large number of asymptomatic infections.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012703"},"PeriodicalIF":5.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11578500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683267","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":"TMPRSS2 in microbial interactions: Insights from HKU1 and TcsH.","authors":"Zhengyang Pan, Daoqun Li, Leiliang Zhang","doi":"10.1371/journal.ppat.1012677","DOIUrl":"10.1371/journal.ppat.1012677","url":null,"abstract":"<p><p>Transmembrane Serine Protease 2 (TMPRSS2), known primarily for its role as a protease, has emerged as a critical receptor for microbial agents such as human coronavirus HKU1 and exotoxin TcsH. HKU1 utilizes both sialoglycan and TMPRSS2 for cellular entry, where sialoglycan primes the spike protein for TMPRSS2 binding. TMPRSS2 undergoes autocleavage to enhance its affinity for the HKU1 spike, facilitating viral membrane fusion postcleavage. Interestingly, TMPRSS2's catalytic function is dispensable for both HKU1 and TcsH interactions, suggesting alternative roles in pathogenesis. Structural insights highlight potential therapeutic targets against viral infections and cancers, leveraging TMPRSS2 interactions for drug development. Understanding the interplay between TMPRSS2 and microbes opens new avenues for targeting TMPRSS2 in developing treatments for infections.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012677"},"PeriodicalIF":5.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11578487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682220","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":"The Cryptococcus neoformans STRIPAK complex controls genome stability, sexual development, and virulence.","authors":"Patricia P Peterson, Jin-Tae Choi, Ci Fu, Leah E Cowen, Sheng Sun, Yong-Sun Bahn, Joseph Heitman","doi":"10.1371/journal.ppat.1012735","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012735","url":null,"abstract":"<p><p>The eukaryotic serine/threonine protein phosphatase PP2A is a heterotrimeric enzyme composed of a scaffold A subunit, a regulatory B subunit, and a catalytic C subunit. Of the four known B subunits, the B\"' subunit (known as striatin) interacts with the multi-protein striatin-interacting phosphatase and kinase (STRIPAK) complex. Orthologs of STRIPAK components were identified in Cryptococcus neoformans, namely PP2AA/Tpd3, PP2AC/Pph22, PP2AB/Far8, STRIP/Far11, SLMAP/Far9, and Mob3. Structural modeling, protein domain analysis, and detected protein-protein interactions suggest C. neoformans STRIPAK is assembled similarly to the human and fungal orthologs. Here, STRIPAK components Pph22, Far8, and Mob3 were functionally characterized. Whole-genome sequencing revealed that mutations in STRIPAK complex subunits lead to increased segmental and chromosomal aneuploidy, suggesting STRIPAK functions in maintaining genome stability. We demonstrate that PPH22 is a haploinsufficient gene: heterozygous PPH22/pph22Δ mutant diploid strains exhibit defects in hyphal growth and sporulation and have a significant fitness disadvantage when grown in competition against a wild-type diploid. Deletion mutants pph22Δ, far8Δ, and mob3Δ exhibit defects in mating and sexual differentiation, including impaired hyphae, basidia, and basidiospore production. Loss of either PPH22 or FAR8 in a haploid background leads to growth defects at 30°C, severely reduced growth at elevated temperature, abnormal cell morphology, and impaired virulence. Additionally, pph22Δ strains frequently accumulate suppressor mutations that result in overexpression of another putative PP2A catalytic subunit, PPG1. The pph22Δ and far8Δ mutants are also unable to grow in the presence of the calcineurin inhibitors cyclosporine A or FK506, and thus these mutations are synthetically lethal with loss of calcineurin activity. Conversely, mob3Δ mutants display increased thermotolerance, capsule production, and melanization, and are hypervirulent in a murine infection model. Taken together, these findings reveal that the C. neoformans STRIPAK complex plays an important role in genome stability, vegetative growth, sexual development, and virulence in this prominent human fungal pathogen.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012735"},"PeriodicalIF":5.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677399","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":"Antagonism of BST2/Tetherin, a new restriction factor of respiratory syncytial virus, requires the viral NS1 protein.","authors":"Katherine Marougka, Delphine Judith, Tristan Jaouen, Sabine Blouquit-Laye, Gina Cosentino, Clarisse Berlioz-Torrent, Marie-Anne Rameix-Welti, Delphine Sitterlin","doi":"10.1371/journal.ppat.1012687","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012687","url":null,"abstract":"<p><p>Human respiratory syncytial virus (RSV) is an enveloped RNA virus and the leading viral agent responsible for severe pediatric respiratory infections worldwide. Identification of cellular factors able to restrict viral infection is one of the key strategies used to design new drugs against infection. Here, we report for the first time that the cellular protein BST2/Tetherin (a widely known host antiviral molecule) behaves as a restriction factor of RSV infection. We showed that BST2 silencing resulted in a significant rise in viral production during multi-cycle infection, suggesting an inhibitory role during the late steps of RSV's multiplication cycle. Conversely, BST2 overexpression resulted in diminution of the viral production. Furthermore, BST2 was found associated with envelope proteins and co-localized with viral filaments, suggesting that BST2 tethers RSV particles. Interestingly, RSV naturally downregulates cell surface and global BST2 expression, possibly through a mechanism dependent on ubiquitin. RSV's ability to enhance BST2 degradation was also validated in a model of differentiated cells infected by RSV. Additionally, we found that a virus deleted of NS1 is unable to downregulate BST2 and is significantly more susceptible to BST2 restriction compared to the wild type virus. Moreover, NS1 and BST2 interact in a co- immunoprecipitation experiment. Overall, our data support a model in which BST2 is a restriction factor against RSV infection and that the virus counteracts this effect by limiting the cellular factor's expression through a mechanism involving the viral protein NS1.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012687"},"PeriodicalIF":5.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677395","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":"AGC family kinase of Entamoeba histolytica: Decoding the members biochemically.","authors":"Azhar Ahmad, Vikas Kumar, Tushar Kushwaha, Akash Kumar, Deepak Sehgal, Krishna K Inampudi, Somlata","doi":"10.1371/journal.ppat.1012729","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012729","url":null,"abstract":"<p><p>Entamoeba histolytica, a protozoan parasite, is the causative agent of amoebiasis, which is a significant global health concern. The virulence mechanisms underlying its pathogenicity are multifaceted and complex. However, endocytic processes and motility are well accepted virulence determinants. As previously reported, an AGCK family kinase, EhAGCK1 to be involved in trogocytosis exclusively while another one from same family named EhAGCK2 participates in all actin dependent endocytic processes. As the kinase dead mutants of EhAGCK1 showed significant defect in destruction of live host cells and also the localisation pattern of same is distinguishable from EhAGCK2. From observations so far, it appears that former initiates a distinguishable signaling cascade. In this work, we have demonstrated distinct biochemical properties of kinases involved in related yet distinguishable endocytic processes for the first time. Our biochemical characterization highlights distinct ion dependency of EhAGCK1 along with substrate specificity. We also show upstream activator of these kinases, 3-phosphoinositide dependent kinase 1 (PDK1) activity and its role in activating the kinase activity. The kinases exhibit property of autophosphorylation, and which may regulate the kinase activity subsequently. Summarily, these studies show that EhAGCK1 and EhAGCK2 show distinct biochemical properties which further confirm their unique role in related endocytic processes of trogocytosis and phagocytosis.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012729"},"PeriodicalIF":5.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677127","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}