PLoS Pathogens最新文献

{"title":"Mutations in chikungunya virus nsP4 decrease viral fitness and sensitivity to the broad-spectrum antiviral 4'-Fluorouridine.","authors":"Peiqi Yin, Elizabeth B Sobolik, Nicholas A May, Sainan Wang, Atef Fayed, Dariia Vyshenska, Adam M Drobish, M Guston Parks, Laura Sandra Lello, Andres Merits, Thomas E Morrison, Alexander L Greninger, Margaret Kielian","doi":"10.1371/journal.ppat.1012859","DOIUrl":"10.1371/journal.ppat.1012859","url":null,"abstract":"<p><p>Chikungunya virus (CHIKV) is an arthritogenic alphavirus that has re-emerged to cause large outbreaks of human infections worldwide. There are currently no approved antivirals for treatment of CHIKV infection. Recently, we reported that the ribonucleoside analog 4'-fluorouridine (4'-FlU) is a highly potent inhibitor of CHIKV replication, and targets the viral nsP4 RNA dependent RNA polymerase. In mouse models, oral therapy with 4'-FlU diminished viral tissue burdens and virus-induced disease signs. To provide critical evidence for the potential of 4'-FlU as a CHIKV antiviral, here we selected for CHIKV variants with decreased 4'-FlU sensitivity, identifying two pairs of mutations in nsP2 and nsP4. The nsP4 mutations Q192L and C483Y were predominantly responsible for reduced sensitivity. These variants were still inhibited by higher concentrations of 4'-FlU, and the mutations did not change nsP4 fidelity or provide a virus fitness advantage in vitro or in vivo. Pathogenesis studies in mice showed that the nsP4-C483Y variant caused similar disease and viral tissue burden as WT CHIKV, while the nsP4-Q192L variant was strongly attenuated. Together these results support the potential of 4'-FlU to be an important antiviral against CHIKV.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012859"},"PeriodicalIF":5.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980324","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":"Casein Kinases 2-dependent phosphorylation of the placental ligand VAR2CSA regulates Plasmodium falciparum-infected erythrocytes cytoadhesion.","authors":"Dominique Dorin-Semblat, Jean-Philippe Semblat, Romain Hamelin, Anand Srivastava, Marilou Tetard, Graziella Matesic, Christian Doerig, Benoit Gamain","doi":"10.1371/journal.ppat.1012861","DOIUrl":"10.1371/journal.ppat.1012861","url":null,"abstract":"<p><p>Placental malaria is characterized by the massive accumulation and sequestration of infected erythrocytes in the placental intervillous blood spaces, causing severe birth outcomes. The variant surface antigen VAR2CSA is associated with Plasmodium falciparum sequestration in the placenta via its capacity to adhere to chondroitin sulfate A. We have previously shown that the extracellular region of VAR2CSA is phosphorylated on several residues and that the phosphorylation enhances the adhesive properties of CSA-binding infected erythrocytes. Here, we aimed to identify the kinases mediating this phosphorylation. We report that Human and Plasmodium falciparum Casein Kinase 2α are involved in the phosphorylation of the extracellular region of VAR2CSA. We notably show that both CK2α can phosphorylate the extracellular region of recombinant and immunoprecipitated VAR2CSA. Mass spectrometry analysis of recombinant VAR2CSA phosphorylated by recombinant Human and P. falciparum CK2α combined with site-directed mutagenesis led to the identification of residue S1068 in VAR2CSA, which is phosphorylated by both enzymes and is associated with CSA binding. Furthermore, using CRISPR/Cas9 we generated a parasite line in which phosphoresidue S1068 was changed to alanine. This mutation strongly impairs infected erythrocytes adhesion by abolishing VAR2CSA translocation to the surface of infected erythrocytes. We also report that two specific CK2 inhibitors reduce infected erythrocytes adhesion to CSA and decrease the phosphorylation of the recombinant extracellular region of VAR2CSA using either infected erythrocytes lysates as a source of kinases or recombinant Human and P. falciparum casein kinase 2. Taken together, these results undoubtedly demonstrate that host and P. falciparum CK2α phosphorylate the extracellular region of VAR2CSA and that this post-translational modification is important for VAR2CSA trafficking and for infected erythrocytes adhesion to CSA.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012861"},"PeriodicalIF":5.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980315","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":"Calcium-mediated mitochondrial fission and mitophagy drive glycolysis to facilitate arterivirus proliferation.","authors":"Zhe Sun, Zicheng Ma, Wandi Cao, Chenlong Jiang, Lei Guo, Kesen Liu, Yanni Gao, Juan Bai, Jiang Pi, Ping Jiang, Xing Liu","doi":"10.1371/journal.ppat.1012872","DOIUrl":"10.1371/journal.ppat.1012872","url":null,"abstract":"<p><p>Mitochondria, recognized as the \"powerhouse\" of cells, play a vital role in generating cellular energy through dynamic processes such as fission and fusion. Viruses have evolved mechanisms to hijack mitochondrial function for their survival and proliferation. Here, we report that infection with the swine arterivirus porcine reproductive and respiratory syndrome virus (PRRSV), manipulates mitochondria calcium ions (Ca2+) to induce mitochondrial fission and mitophagy, thereby reprogramming cellular energy metabolism to facilitate its own replication. Mechanistically, PRRSV-induced mitochondrial fission is caused by elevated levels of mitochondria Ca2+, derived from the endoplasmic reticulum (ER) through inositol 1,4,5-triphosphate receptor (IP3R)-voltage-dependent anion channel 1 (VDAC1)-mitochondrial calcium uniporter (MCU) channels. This process is associated with increased mitochondria-associated membranes (MAMs), mediated by the upregulated expression of sigma non-opioid intracellular receptor 1 (SIGMAR1). Elevated mitochondria Ca2+ further activates the Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ)-AMP-activated protein kinase (AMPK)-dynamin-related protein 1 (DRP1) signaling pathway, which interacts with mitochondrial fission protein 1 (FIS1) and mitochondrial dynamics proteins of 49 kDa (MiD49) to promote mitochondrial fission. PRRSV infection, alongside mitochondrial fission, triggers mitophagy via the PTEN-induced putative kinase 1 (PINK1)-Parkin RBR E3 ubiquitin (Parkin) pathway, promoting cellular glycolysis and excessive lactate production to facilitate its own replication. This study reveals the mechanism by which mitochondrial Ca2+ regulates mitochondrial function during PRRSV infection, providing new insights into the interplay between the virus and host cell metabolism.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012872"},"PeriodicalIF":5.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980313","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":"SIV Env RhmAbs + N-803 at ART initiation prolongs viral decay without disrupting reservoir establishment in SIV-infected infant macaques.","authors":"Omotayo Farinre, Tzoalli Anaya, Alexis C King, Kedan Endrias, Anne H Hébert, Alison L Hill, Sherrie Jean, Jennifer S Wood, Stephanie Ehnert, Shan Liang, Gregory M Laird, Rosemarie D Mason, Mario Roederer, Jeffrey T Safrit, Maud Mavigner, Ann Chahroudi","doi":"10.1371/journal.ppat.1012863","DOIUrl":"10.1371/journal.ppat.1012863","url":null,"abstract":"<p><p>The latent viral reservoir remains the major barrier to HIV cure, placing the burden of strict adherence to antiretroviral therapy (ART) on people living with HIV to prevent recrudescence of viremia. For infants with perinatally acquired HIV, adherence is anticipated to be a lifelong need. In this study, we tested the hypothesis that administration of ART and viral Envelope-specific rhesus-derived IgG1 monoclonal antibodies (RhmAbs) with or without the IL-15 superagonist N-803 early in infection would limit viral reservoir establishment in SIV-infected infant rhesus macaques. Following initiation of ART at 1-2 weeks after oral SIVmac251 infection, we observed biphasic decay of viremia, with first phase decay significantly faster in the ART + SIV RhmAbs-treated group compared to controls that received only ART. In contrast, the addition of N-803 to ART + SIV RhmAbs significantly slowed both the first and second phase viral decay compared to the ART only group. Treatment with a single dose of N-803 resulted in increased frequency of Ki67 expressing NK, CD8+, and CD4+ T cells. Levels of intact SIV proviruses in CD4+ T cells from blood, lymph nodes, and rectum at week 48 of ART did not differ across groups. Similarly, the time to viral rebound following ART interruption was not impacted by the experimental treatments. These results support the concept that the rebound-competent viral reservoir is formed within days after infection and that targeting only productively infected cells for clearance near the time of ART initiation, even during acute infection, may be insufficient to limit reservoir establishment.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012863"},"PeriodicalIF":5.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962512","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":"SLC35A2 gene product modulates paramyxovirus fusion events during infection.","authors":"Yanling Yang, Yuchen Wang, Danielle E Campbell, Heng-Wei Lee, Wandy Beatty, Leran Wang, Megan Baldridge, Carolina B López","doi":"10.1371/journal.ppat.1012531","DOIUrl":"10.1371/journal.ppat.1012531","url":null,"abstract":"<p><p>Paramyxoviruses are significant human and animal pathogens that include mumps virus (MuV), Newcastle disease virus (NDV) and the murine parainfluenza virus Sendai (SeV). Despite their importance, few host factors implicated in paramyxovirus infection are known. Using a recombinant SeV expressing destabilized eGFP (rSeVCdseGFP) in a loss-of-function CRISPR screen, we identified the CMP-sialic acid transporter (CST) gene SLC35A1 and the UDP-galactose transporter (UGT) gene SLC35A2 as essential for paramyxovirus infection. As expected, SLC35A1 knockout (KO) cells showed drastic reduction in infections with SeV, NDV and MuV due to the lack of cell surface sialic acids receptors. However, SLC35A2 KO cells revealed unknown critical roles for this factor in virus-cell and cell-to-cell fusion events for the different paramyxoviruses. While UGT was essential for virus-cell fusion during SeV entry to the cell, it was not required for NDV or MuV entry. Importantly, UGT promoted the formation of syncytia during MuV infection, suggesting a role in cell-to-cell virus spread. Our findings demonstrate that paramyxoviruses can bind to or enter A549 cells in the absence of canonical galactose-bound sialic-acid decorations and show that UGT facilitates paramyxovirus fusion processes involved in entry and spread.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012531"},"PeriodicalIF":5.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962514","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":"Transcriptomic HIV-1 reservoir profiling reveals a role for mitochondrial functionality in HIV-1 latency.","authors":"Shirley Man, Jade Jansen, Stefanie Kroeze, Teunis B H Geijtenbeek, Neeltje A Kootstra","doi":"10.1371/journal.ppat.1012822","DOIUrl":"10.1371/journal.ppat.1012822","url":null,"abstract":"<p><p>Identifying cellular and molecular mechanisms maintaining HIV-1 latency in the viral reservoir is crucial for devising effective cure strategies. Here we developed an innovative flow cytometry-fluorescent in situ hybridization (flow-FISH) approach for direct ex vivo reservoir detection without the need for reactivation using a combination of probes detecting abortive and elongated HIV-1 transcripts. Our flow-FISH assay distinguished between HIV-1-infected CD4+ T cells expressing abortive or elongated HIV-1 transcripts in PBMC from untreated and ART-treated PWH from the Amsterdam Cohort Studies. This flow-FISH method was employed to isolate CD4+ T cells expressing abortive or elongated HIV-1 transcripts from five ART-naïve PWH for transcriptomic analysis by 3' RNA sequencing. Supervised cluster analysis identified several differentially expressed mitochondrial genes in infected CD4+ T cells with abortive HIV-1 transcripts compared to cells containing elongated HIV-1 transcripts. Notably, enhancing mitochondrial function induced HIV-1 transcription in PBMC from PWH. Our data strongly suggests that cellular metabolism is involved in maintaining HIV-1 latency and show that improving mitochondrial functions induces HIV-1 transcriptional activity in PWH. These findings underline the relevance of metabolic regulation in HIV-1 infection, and support the development of strategies modulating immunometabolism to target viral latency.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012822"},"PeriodicalIF":5.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11723532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962515","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 Helicobacter pylori flagellar motor accessory is needed to maintain the barrier function of the outer membrane during flagellar rotation.","authors":"Kyle Rosinke, Shoichi Tachiyama, Jan Mrásek, Jun Liu, Timothy R Hoover","doi":"10.1371/journal.ppat.1012860","DOIUrl":"10.1371/journal.ppat.1012860","url":null,"abstract":"<p><p>The Helicobacter pylori flagellar motor contains several accessory structures that are not found in the archetypal Escherichia coli and Salmonella enterica motors. H. pylori hp0838 encodes a previously uncharacterized lipoprotein and is in an operon with flgP, which encodes a motor accessory protein. Deletion analysis of hp0838 in H. pylori B128 showed that the gene is not required for motility in soft agar medium, but the mutant displayed a reduced growth rate and an increased sensitivity to bacitracin, which is an antibiotic that is normally excluded by the outer membrane. Introducing a plasmid-borne copy of hp0838 into the H. pylori Δhp0838 mutant suppressed the fitness defect and antibiotic sensitivity of the strain. A variant of the Δhp0838 mutant containing a frameshift mutation in pflA, which resulted in paralyzed flagella, displayed wild-type growth rate and resistance to bacitracin, suggesting the fitness defect and antibiotic sensitivity of the Δhp0838 mutant are dependent on flagellar rotation. Comparative analysis of in-situ structures of the wild type and Δhp0838 mutant motors revealed the Δhp0838 mutant motor lacked a previously undescribed ring structure with 18-fold symmetry located near the outer membrane. Given its role in formation of the motor outer ring, HP0838 was designated FapH (flagellar accessory protein in Helicobacter pylori) and the motor accessory formed the protein was named the FapH ring. Our data suggest that the FapH ring helps to preserve outer membrane barrier function during flagellar rotation. Given that FapH homologs are present in many members of the phylum Campylobacterota, they may have similar roles in protecting the outer membrane from damage due to flagellar rotation in these bacteria.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012860"},"PeriodicalIF":5.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962509","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":"Breaking a barrier: In trans vlsE recombination and genetic manipulation of the native vlsE gene of the Lyme disease pathogen.","authors":"Preeti Singh, Troy Bankhead","doi":"10.1371/journal.ppat.1012871","DOIUrl":"10.1371/journal.ppat.1012871","url":null,"abstract":"<p><p>Host-pathogen interactions represent a dynamic evolutionary process, wherein both hosts and pathogens continuously develop complex mechanisms to outmaneuver each other. Borrelia burgdorferi, the Lyme disease pathogen, has evolved an intricate antigenic variation mechanism to evade the host immune response, enabling its dissemination, persistence, and pathogenicity. Despite the discovery of this mechanism over two decades ago, the precise processes, genetic elements, and proteins involved in this system remain largely unknown. The vls locus, which is the site of antigenic variation, has been notoriously challenging to manipulate genetically due to its highly conserved structural features, even with significant advancements in molecular biology and genetic engineering for this highly segmented pathogen. Our study highlights the pivotal role of plasmid topology in facilitating in trans gene recombination. We demonstrate that gene conversion can occur in trans when a copy of vlsE gene is present on a linear plasmid, contrary to previous observations suggesting a cis arrangement is required for vlsE recombination. Significantly, employing this in trans gene conversion strategy with a linear plasmid, we have, for the first time, achieved targeted genetic mutation of putative cis-acting elements in the native vlsE gene. This has unveiled a potentially crucial role for the 17 bp direct repeats that flank the central variable cassette region of vlsE. Furthermore, we validated the reliability and reproducibility of our mutational approach by successfully inserting stop codons at two distinct sites within the central variable cassette of vlsE. Thus, this study presents a significant methodological innovation enabling the direct manipulation of the vls locus and lays the groundwork for systematic exploration of specific mutations affecting the mechanism of antigenic variation. As a result, it creates new avenues for research and raises intriguing questions that could guide the development of novel methods to explore host-pathogen interactions of the agent of Lyme disease.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012871"},"PeriodicalIF":5.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962511","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":"Hepatitis B virus genotypes A1 and A2 have distinct replication phenotypes due to polymorphisms in the HBx gene.","authors":"Min Zhang, Karim Mouzannar, Zhensheng Zhang, Yuji Teraoka, Jason Piotrowski, Yuji Ishida, Chise Tateno-Mukaidani, Takeshi Saito, Hiromi Abe-Chayama, Kazuaki Chayama, T Jake Liang","doi":"10.1371/journal.ppat.1012803","DOIUrl":"10.1371/journal.ppat.1012803","url":null,"abstract":"<p><p>HBV genotype A has two major subtypes, A1 (commonly in Africa) and A2 (commonly in Europe) with only 4% nucleotide differences. Individuals infected with these two subtypes appear to have different clinical manifestations and virologic features. Whether such a difference results from the virus or host has not been established. Using HBV generated from molecule clones of subtypes A1 and A2 in cell culture (HBVcc), we demonstrate that HBVcc of subtypes A1 and A2 can be passaged in vitro and in vivo and respond equally well to human IFN-α treatment. HBVcc passaged in human liver chimeric mice (HBVmp) infected human hepatocytes more efficiently than that of the original HBVcc. Subtype A2 showed a much higher viral replication level than that of subtype A1. Mechanistic investigations using constructs with chimeric A1/A2 sequences and specific mutations indicated that subtype A2 has an inherently higher replication phenotype due to specific polymorphisms in the HBx gene resulting in amino acid variations. Studies of HBx expression demonstrated that A1 HBx is expressed at a much lower level than that of A2 HBx. Mutagenesis studies identified two HBx amino acid variations responsible for the observed phenotypic difference. Using AlphaFold2, we generated structural models of HBx proteins of A1 and A2. Superposition of the two models reveal that the overall structural motifs are similarly aligned, except for the C-terminal peptides diverging between the A1 and A2 models, possibly explaining their functional difference. In conclusion, using various in vitro and in vivo models, here we show that subtype A2 has an inherently higher replication phenotype due to polymorphisms in HBx that result in possible differences in structure and expression level of the two subtype HBx proteins. This genotypic difference potentially explains the reported clinical differences between the two subtypes as well as providing a previously unrecognized association between viral sequence variations and clinical manifestations of HBV infection in humans.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012803"},"PeriodicalIF":5.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957346","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 conserved fungal Knr4/Smi1 protein is crucial for maintaining cell wall stress tolerance and host plant pathogenesis.","authors":"Erika Kroll, Carlos Bayon, Jason Rudd, Victoria J Armer, Anjana Magaji-Umashankar, Ryan Ames, Martin Urban, Neil A Brown, Kim Hammond-Kosack","doi":"10.1371/journal.ppat.1012769","DOIUrl":"10.1371/journal.ppat.1012769","url":null,"abstract":"<p><p>Filamentous plant pathogenic fungi pose significant threats to global food security, particularly through diseases like Fusarium Head Blight (FHB) and Septoria Tritici Blotch (STB) which affects cereals. With mounting challenges in fungal control and increasing restrictions on fungicide use due to environmental concerns, there is an urgent need for innovative control strategies. Here, we present a comprehensive analysis of the stage-specific infection process of Fusarium graminearum in wheat spikes by generating a dual weighted gene co-expression network (WGCN). Notably, the network contained a mycotoxin-enriched fungal module (F12) that exhibited a significant correlation with a detoxification gene-enriched wheat module (W12). This correlation in gene expression was validated through quantitative PCR. By examining a fungal module with genes highly expressed during early symptomless infection that was correlated to a wheat module enriched in oxidative stress genes, we identified a gene encoding FgKnr4, a protein containing a Knr4/Smi1 disordered domain. Through comprehensive analysis, we confirmed the pivotal role of FgKnr4 in various biological processes, including oxidative stress tolerance, cell cycle stress tolerance, morphogenesis, growth, and pathogenicity. Further studies confirmed the observed phenotypes are partially due to the involvement of FgKnr4 in regulating the fungal cell wall integrity pathway by modulating the phosphorylation of the MAP-kinase MGV1. Orthologues of the FgKnr4 gene are widespread across the fungal kingdom but are absent in other Eukaryotes, suggesting the protein has potential as a promising intervention target. Encouragingly, the restricted growth and highly reduced virulence phenotypes observed for ΔFgknr4 were replicated upon deletion of the orthologous gene in the wheat fungal pathogen Zymoseptoria tritici. Overall, this study demonstrates the utility of an integrated network-level analytical approach to pinpoint genes of high interest to pathogenesis and disease control.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012769"},"PeriodicalIF":5.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957324","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}