PLoS Pathogens最新文献

{"title":"Antibiotics change the population growth rate heterogeneity and morphology of bacteria.","authors":"Morten Kals, Emma Kals, Jurij Kotar, Allen Donald, Leonardo Mancini, Pietro Cicuta","doi":"10.1371/journal.ppat.1012924","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012924","url":null,"abstract":"<p><p>A better understanding of the system-level effects of antibiotics on bacterial cells is essential to address the growing challenge of antibiotic resistance. Utilising Multipad Agarose Plate (MAP) platforms, we monitor the growth rate and cell morphology of three clinically relevant species (E.coli, S.aureus and P.aeruginosa) following exposure to 14 antibiotics across 11 concentrations (31 microbe-antibiotic combinations in total). Our results reveal a consistent increase in population growth rate heterogeneity (PGRH) as drug concentrations approach the minimum inhibitory concentration (MIC). Strikingly, the magnitude of this heterogeneity correlates with the functional distance between the ribosome and the specific cellular processes targeted by the antibiotics. Among the seven antibiotic classes studied, protein synthesis inhibitors and disruptors cause the lowest PGRH, while heterogeneity progressively increases with RNA synthesis inhibitors, DNA replication inhibitors, cell membrane disruptors and cell wall synthesis inhibitors. Because the ribosome is central to growth rate control, we hypothesize that heterogeneity might arise at the system level as a result of the propagation of damage to protein synthesis. Low heterogeneity is desirable from a clinical perspective, as high heterogeneity is often associated with persistence and treatment survival. Additionally, we observed a strong correlation between morphological alterations and growth inhibition across all antibiotics and species tested. This led to the development of a novel morphological parameter, MOR50, which enables rapid estimation of MIC for antibiotic susceptibility testing (AST) with a single snapshot after just 2.5 hours of incubation. In addition to introducing a novel, resource-efficient and rapid AST method, our findings shed new light on the system-level effects of antibiotic perturbations on bacteria, which might inform treatment design.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012924"},"PeriodicalIF":5.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257055","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":"Imprudent use of MalAvi names biases the estimation of parasite diversity of avian haemosporidians.","authors":"Juliana Tamayo-Quintero, Josué Martínez-de la Puente, Nubia E Matta, M Andreína Pacheco, Héctor F Rivera-Gutierrez","doi":"10.1371/journal.ppat.1012911","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012911","url":null,"abstract":"","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012911"},"PeriodicalIF":5.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257057","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":"CCR2 signaling regulates anti-chlamydia T cell immune responses in the airway.","authors":"Shuaini Yang, Jinxi Yu, Xue Dong, Jiajia Zeng, Lu Tan, Hong Zhang, Ruoyuan Sun, Yuqing Tuo, Jing Yang, Chunxiao Wan, Hong Bai","doi":"10.1371/journal.ppat.1012912","DOIUrl":"10.1371/journal.ppat.1012912","url":null,"abstract":"<p><p>CCR2, a member of the G protein-coupled receptor (GPCR) superfamily, is widely expressed on monocytes, macrophages, activated T cells, and other cell types, and plays a critical role in coordinating the immune response to various infections. Here we demonstrate that CCR2 expression is significantly elevated during Chlamydia muridarum (C. muridarum) respiratory infection, and its absence leads to exacerbated susceptibility, as evidenced by significant weight loss, higher bacterial loads, severe lung pathology, and elevated levels of inflammatory cytokines (il-1β, tnfα, and il-6). The absence of ccr2 impairs both myeloid cell infiltration and T cell responses, which are crucial for effective immune defense. Specifically, ccr2 deficiency disrupts the differentiation and response of Th1 cells, which are the primary effector lineage responsible for clearing chlamydia through secretion of interferon-gamma (IFN-γ). As a result, there is a significant decrease in CD3+CD4+IFN-γ+ T cells in the lung and spleen, accompanied by reduced levels of IFN-γ protein and mRNA, as well as downregulated mRNA expression of Th1-promoting cytokines (il-12p35, il-12p40) and transcription factors (stat4, T-bet), which play crucial roles in Th1 differentiation. Moreover, ccr2 deficiency greatly diminishes STAT1 phosphorylation, a key regulator of IFN-γ secretion by Th1 cells. Meanwhile, we also observed a significant reduction in IFN-γ secretion by CD8+ T cells following ccr2 deficiency. Conversely, ccr2-/- mice exhibit an exaggerated Th2-type immune response, with elevated levels of Th2-promoting cytokines (IL-4), transcription factors (STAT6 and gata3), and il-5, which together lead to more severe lung tissue damage and increased susceptibility to infection. Furthermore, these mice show higher levels of IL-17 along with an enhanced Th17-type immune response, characterized by increased Th17-promoting cytokines TGFB, transcription factors stat3 and RORγt, and il-21, suggesting a compensatory mechanism that drives neutrophil infiltration to exacerbate lung inflammation. These findings underscore the pivotal role of CCR2, a chemokine receptor, in orchestrating the immune response to Chlamydia infection by facilitating Th1 cells differentiation while restraining Th2-type and Th17-type immune responses, thereby alleviating pulmonary inflammation.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012912"},"PeriodicalIF":5.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189956","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":"Increased NFAT and NFκB signalling contribute to the hyperinflammatory phenotype in response to Aspergillus fumigatus in a mouse model of cystic fibrosis.","authors":"Amelia Bercusson, Thomas J Williams, Nicholas J Simmonds, Eric Wfw Alton, Uta Griesenbach, Anand Shah, Adilia Warris, Darius Armstrong-James","doi":"10.1371/journal.ppat.1012784","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012784","url":null,"abstract":"<p><p>Aspergillus fumigatus (Af) is a major mould pathogen found ubiquitously in the air. It commonly infects the airways of people with cystic fibrosis (CF) leading to Aspergillus bronchitis or allergic bronchopulmonary aspergillosis. Resident alveolar macrophages and recruited neutrophils are important first lines of defence for clearance of Af in the lung. However, their contribution to the inflammatory phenotype in CF during Af infection is not well understood. Here, utilising CFTR deficient mice we describe a hyperinflammatory phenotype in both acute and allergic murine models of pulmonary aspergillosis. We show that during aspergillosis, CFTR deficiency leads to increased alveolar macrophage death and persistent inflammation of the airways in CF, accompanied by impaired fungal control. Utilising CFTR deficient murine cells and primary human CF cells we show that at a cellular level there is increased activation of NFκB and NFAT in response to Af which, as in in vivo models, is associated with increased cell death and reduced fungal control. Taken together, these studies indicate that CFTR deficiency promotes increased activation of inflammatory pathways, the induction of macrophage cell death and reduced fungal control contributing to the hyper-inflammatory of pulmonary aspergillosis phenotypes in CF.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012784"},"PeriodicalIF":5.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190455","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":"Sexual recombination in cereal rust fungi: Knowns and unknowns of pathogen evolution and adaptation.","authors":"Shideh Mojerlou, Benjamin Schwessinger, Julian Rodriguez-Algaba","doi":"10.1371/journal.ppat.1012908","DOIUrl":"10.1371/journal.ppat.1012908","url":null,"abstract":"","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012908"},"PeriodicalIF":5.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190577","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 paradoxical population structure of var DBLα types in Africa.","authors":"Mun Hua Tan, Kathryn E Tiedje, Qian Feng, Qi Zhan, Mercedes Pascual, Heejung Shim, Yao-Ban Chan, Karen P Day","doi":"10.1371/journal.ppat.1012813","DOIUrl":"10.1371/journal.ppat.1012813","url":null,"abstract":"<p><p>The var multigene family encodes Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), central to host-parasite interactions. Genome structure studies have identified three major groups of var genes by specific upstream sequences (upsA, B, or C). Var with these ups groups have different chromosomal locations, transcriptional directions, and associations with disease severity. Here we explore temporal and spatial diversity of a region of var genes encoding the DBLα domain of PfEMP1 in Africa. By applying a novel ups classification algorithm (cUps) to publicly-available DBLα sequence datasets, we categorised DBLα according to association with the three ups groups, thereby avoiding the need to sequence complete genes. Data from deep sequencing of DBLα types in a local population in northern Ghana surveyed seven times from 2012 to 2017 found variants with rare-to-moderate-to-extreme frequencies, and the common variants were temporally stable in this local endemic area. Furthermore, we observed that every isolate repertoire, whether mono- or multiclonal, comprised DBLα types occurring with these frequency ranges implying a common genome structure. When comparing African countries of Ghana, Gabon, Malawi, and Uganda, we report that some DBLα types were consistently found at high frequencies in multiple African countries while others were common only at the country level. The implication of these local and pan-Africa population patterns is discussed in terms of advantage to the parasite with regards to within-host adaptation and resilience to malaria control.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012813"},"PeriodicalIF":5.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191130","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-like particles encapsidate RNA and exhibit decreased stability due to lack of maturation.","authors":"Louis Kuijpers, Evdokia-Anastasia Giannopoulou, Yuzhen Feng, Wouter van den Braak, Abbas Freydoonian, Ramon Ramlal, Hugo Meiring, Belén Solano, Wouter H Roos, Arjen J Jakobi, Leo A van der Pol, Nynke H Dekker","doi":"10.1371/journal.ppat.1012873","DOIUrl":"10.1371/journal.ppat.1012873","url":null,"abstract":"<p><p>To counteract hand, foot, and mouth disease-causing viruses such as enterovirus A71 and coxsackievirus A6, virus-like particles (VLPs) have emerged as a leading contender for the development of a multivalent vaccine. However, VLPs have shown rapid conversion from a highly immunogenic state to a less immunogenic state and low particle integrity lifetimes compared to inactivated virus vaccines, thus raising concerns about their overall stability. Here, we produce VLPs to investigate capsid stability using cryogenic electron microscopy (cryo-EM), mass spectrometry (MS), biochemical assays, and atomic force microscopy (AFM). In contrast to prior studies and prevailing hypotheses, we show that insect-cell produced enterovirus VLPs include encapsidated RNA fragments with viral protein coding sequences. Our integrated approach reveals that CVA6 VLPs do not undergo viral maturation, in contrast to virions; that they can encapsidate RNA fragments, similarly to virions; and that despite the latter, they are more brittle than virions. Interestingly, this indicates that CVA6 VLP stability is more affected by lack of viral maturation than the presence of RNA. Our study highlights how the development of VLPs as vaccine candidates should encompass probing for unwanted (viral) RNA content and establishing control of their maturation to enhance stability.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012873"},"PeriodicalIF":5.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190377","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":"Decoding Cryptococcus: From African biodiversity to worldwide prevalence.","authors":"Marco A Coelho, Márcia David-Palma, Janneke Aylward, Nam Q Pham, Cobus M Visagie, Taygen Fuchs, Neriman Yilmaz, Francois Roets, Sheng Sun, John W Taylor, Brenda D Wingfield, Matthew C Fisher, Michael J Wingfield, Joseph Heitman","doi":"10.1371/journal.ppat.1012876","DOIUrl":"10.1371/journal.ppat.1012876","url":null,"abstract":"","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012876"},"PeriodicalIF":5.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123933","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":"Streptococcus mutans regulates ubiquitin modification of Candida albicans in the bacterial-fungal interaction.","authors":"Yixin Zhang, Zhen Gu, Zhengyi Li, Qinrui Wu, Xin Xu, Xian Peng","doi":"10.1371/journal.ppat.1012887","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012887","url":null,"abstract":"<p><p>The ecological interplay between Streptococcus mutans and Candida albicans within dental plaque biofilms is an important factor driving pathogenesis of dental caries. This study aimed to investigate S. mutans regulation of C. albicans growth and virulence through extracellular membrane vesicles (EMVs) and modulation of ubiquitination, a key protein post-translational modification. We established a transwell co-culture model to enable \"contact-independent\" interactions between S. mutans and C. albicans. S. mutans EMVs were found to directly associate with C. albicans cells and promote biofilm formation and growth. Quantitative ubiquitination profiling revealed S. mutans dramatically alters the ubiquitination landscape in C. albicans. We identified 10,661 ubiquitination sites across the C. albicans proteome and their enrichment in pathways related to translation, metabolism, and stress adaptation. Co-culture with S. mutans led to upregulation of ubiquitination on 398 proteins involved in sugar catabolism and generation of reducing power. S. mutans upregulated ubiquitination of superoxide dismutase-3 of C. albicans, inducing its degradation and heightened reactive oxygen species levels, and concomitantly stimulated C. albicans growth. Our findings elucidate EMVs and ubiquitination modulation as key mechanisms governing the S. mutans-C. albicans interplay and provide new insights into the promotion of a cariogenic oral biofilm environment. This study significantly advances understanding of the complex molecular interactions underlying dental plaque dysbiosis and caries pathogenesis.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012887"},"PeriodicalIF":5.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123938","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":"Marek's disease virus-1 unique gene LORF1 is involved in viral replication and MDV-1/Md5-induced atrophy of the bursa of Fabricius.","authors":"Chenyi Bao, Jun Chu, Qi Gao, Shasha Yang, Xiaoyu Gao, Wenwen Chen, Fuchun Yang, Fei Jiang, Chenxi Tong, Mingyi Lei, Linlin Jiao, Jitong Li, Kexin Wei, Xue Lian, Kai Li, Suresh Kumar Tikoo, Nikolaus Osterrieder, Lorne A Babiuk, Yufeng Li, Yong-Sam Jung, Yingjuan Qian","doi":"10.1371/journal.ppat.1012891","DOIUrl":"10.1371/journal.ppat.1012891","url":null,"abstract":"<p><p>Marek's disease virus (MDV), an alphaherpesvirus, causes severe immunosuppression and T cell lymphomas in chickens, known as Marek's disease (MD), an economically important poultry disease primarily controlled by vaccination. Importantly, it also serves as a comparative model for studying herpesvirus-induced tumor formation in humans. MDV encodes more than 100 genes, most of which have unknown functions. MDV LORF1 is unique to serotype I MDV (MDV-1), lacking homologs in other herpesviruses, and has not been explored yet. To this end, an infectious bacterial artificial chromosome (BAC) harboring the complete genome of the MDV-1 very virulent strain Md5 was generated, and the rescued rMd5 maintained biological properties similar to the parental virus both in vitro and in vivo. Subsequently, rMd5ΔLORF1, a recombinant Md5 virus deficient in pLORF1 expression, was generated by a frameshift mutation in the LORF1 gene. Chickens infected with rMd5ΔLORF1 exhibited a lower mortality rate and delayed bursal atrophy than those infected with the parental rMd5 and the revertant virus (rMd5-reLORF1). Consistently, viral loads of rMd5ΔLORF1 were obviously lower than those of rMd5 or rMd5-reLORF1 in the bursa, but not in the spleen. Importantly, we found that pLORF1 deficiency impairs viral replication in bursal B cells. Furthermore, we showed that pLORF1 associated with the cellular membrane, interacted with MDV structural proteins, and exhibited punctate colocalization with tegument or capsid proteins in the cytoplasm. Taken together, this study demonstrates for the first time that the MDV-1 unique gene LORF1 is involved in MDV-induced bursal atrophy but not in tumor formation.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012891"},"PeriodicalIF":5.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123936","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}