PLoS Pathogens最新文献

{"title":"The Emerging Fungal Pathogen Candida auris Induces IFNγ to Colonize the Skin.","authors":"Diprasom Das, Shrihari M Ganesh, Abtar Mishra, Mihai G Netea, Shankar Thangamani","doi":"10.1371/journal.ppat.1013114","DOIUrl":"10.1371/journal.ppat.1013114","url":null,"abstract":"<p><p>Candida auris is an emerging multidrug-resistant skin-tropic fungal pathogen that causes serious human infections. However, the factors that regulate C. auris skin infection in vivo are still unclear. In this study, we identified that, unlike Candida albicans, which induces IL-17-secreting protective effector Th17 cells, C. auris predominately induces IFNγ-secreting pathogenic Th1 cells during reinfection. Surprisingly, we found that IFNγ enhances skin infection of C. auris but not C. albicans. Mechanistically, IFNγ enhances skin infection of C. auris by dampening the protective IL-17 responses and increasing dermal damage. Furthermore, we identified that the development of Th1 cells occurs through IL-12, produced by C. auris-induced inflammatory macrophages and monocyte-derived dendritic cells. In addition, our findings reveal that C. auris unique cell wall outer mannan layer regulates the development of Th1 and Th17 cells. Collectively, our findings, for the first time, identified that C. auris induces IFNγ to persist in the skin. These findings help explain why C. auris but not C. albicans preferentially persist in the skin long-term, with the potential to identify novel therapeutic approaches to prevent and treat this emerging fungal pathogen in humans.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013114"},"PeriodicalIF":5.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144040039","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":"Deposition of complement regulators on the surface of Plasmodium falciparum merozoites depends on the immune status of the host.","authors":"Maria Rosaria Bassi, Bogdan Cristinoi, Frank Buitenwerf, Mark Bergholt Cuadrado, Kasper Haldrup Björnsson, Melanie Rose Walker, Frederica Dedo Partey, Andrew B Ward, Michael Fokuo Ofori, Lea Barfod","doi":"10.1371/journal.ppat.1013107","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013107","url":null,"abstract":"<p><p>Plasmodium falciparum is responsible for the majority of malaria cases and deaths worldwide. In malaria endemic areas, natural immunity to blood stage infection is acquired over several exposures to the parasite and is thought to rely on antibodies. Antibodies can protect from severe disease through different effector functions, with complement activation lately emerging as an important feature of protective humoral responses to malaria. Plasmodium parasites have however evolved several mechanisms to evade complement attack, including the recruitment of complement down-regulatory proteins like Factor H (FH) and C1 esterase inhibitor (C1-INH). In this study, we report that merozoite-specific antibodies acquired naturally after infection activate the complement cascade in an exposure-dependent manner. Using plasma samples from convalescent children and exposed adults collected respectively in Hohoe and Accra (Ghana), we show that the ability to fix C1q and activate the classical pathway is similar for antibodies deriving from the two donors groups. However, downstream complement activation shown as deposition of the membrane attack complex (MAC) is strikingly higher with antibodies from children compared to antibodies from adults. Moreover, we demonstrate that antibodies from naturally exposed children can interfere with the merozoite recruitment of FH, but not of C1-INH. With the aim of neutralizing parasite evasion of the complement classical pathway, we develop a murine monoclonal antibody targeting PfMSP3, the binding partner of C1-INH on the merozoite surface. We demonstrate that this antibody can effectively block the binding of C1-INH to the parasite surface, unlike the naturally acquired ones. Using cryogenic electron microscopy, we obtain a low-resolution structure of the monoclonal antibody in complex with PfMSP3, which is the first reported structural data for this antigen. We propose targeting parasite antigens binding to complement down-regulators, together with leading vaccine candidate antigens, as a novel strategy to enhance the efficacy of future malaria vaccines.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013107"},"PeriodicalIF":5.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055381","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":"Tailoring mRNA lipid nanoparticles for antifungal vaccines.","authors":"Yeqi Li, Richard B Meagher, Xiaorong Lin","doi":"10.1371/journal.ppat.1013091","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013091","url":null,"abstract":"<p><p>Vaccination is one of the most effective public health measures for preventing and managing infectious diseases. Despite intensive efforts from the relatively small medical mycology community, developing effective vaccines against invasive fungal infections remains a scientific challenge. This is predominantly due to large antigenic repertoires, complicated life cycles, and the capacity of fungal pathogens to evade the host immune system. Additionally, antifungal vaccines often need to work for at-risk individuals who are immunodeficient. We anticipate that the success of mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its exploration for various infectious diseases and cancers will usher a new wave of antifungal vaccine research. Herein, we discuss recent advancements and key scientific areas that need to be explored to actualize the development of effective antifungal mRNA vaccines.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013091"},"PeriodicalIF":5.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038620","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":"In depth sequencing of a serially sampled household cohort reveals the within-host dynamics of Omicron SARS-CoV-2 and rare selection of novel spike variants.","authors":"Emily E Bendall, Derek Dimcheff, Leigh Papalambros, William J Fitzsimmons, Yuwei Zhu, Jonathan Schmitz, Natasha Halasa, James Chappell, Emily T Martin, Jessica E Biddle, Sarah E Smith-Jeffcoat, Melissa A Rolfes, Alexandra Mellis, H Keipp Talbot, Carlos Grijalva, Adam S Lauring","doi":"10.1371/journal.ppat.1013134","DOIUrl":"10.1371/journal.ppat.1013134","url":null,"abstract":"<p><p>SARS-CoV-2 has undergone repeated and rapid evolution to circumvent host immunity. However, outside of prolonged infections in immunocompromised hosts, within-host positive selection has rarely been detected. Here we combine daily longitudinal sampling of individuals with replicate sequencing to increase the accuracy of and lower the threshold for variant calling. We sequenced 577 specimens from 105 individuals in a household cohort during the BA.1/BA.2 variant period. Individuals exhibited extremely low viral diversity, and we estimated a low within-host evolutionary rate. Within-host dynamics were dominated by genetic drift and purifying selection. Positive selection was rare but highly concentrated in spike. A Wright Fisher Approximate Bayesian Computational model identified positive selection at 14 loci with 7 in spike, including S:448 and S:339. This detectable immune-mediated selection is unusual in acute respiratory infections and may be caused by the relatively narrow antibody repertoire in individuals during the early Omicron phase of the SARS-CoV-2 pandemic.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013134"},"PeriodicalIF":5.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12074595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041524","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":"ves1α genes expression is the major determinant of Babesia bovis-infected erythrocytes cytoadhesion to endothelial cells.","authors":"Hassan Hakimi, Junya Yamagishi, Miako Sakaguchi, Atefeh Fathi, Jae Seung Lee, Guilherme G Verocai, Shin-Ichiro Kawazu, Masahito Asada","doi":"10.1371/journal.ppat.1012583","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012583","url":null,"abstract":"<p><p>Babesia bovis causes the most pathogenic form of babesiosis in cattle, resulting in high mortality in naive adults. This parasite invades red blood cells (RBCs) within the bovine hosts where they multiply and produce clinical disease. Babesia bovis exports numerous proteins into invaded RBCs changing its properties. Thus, the infected RBCs (iRBCs) are capable to cytoadhere in the microvasculature of internal organs and brain, leading to respiratory distress, neurologic signs, and mortality. Variant Erythrocyte Surface Antigen 1 (VESA1) is one of those exported proteins by B. bovis which represents a major virulence factor due to its central role in immune evasion by antigenic variation and intravascular parasite sequestration. VESA1 is a heterodimer protein encoded by ves1α and ves1β multigene family and localized on the ridges, the focal point for cytoadhesion. To gain further insights into the molecular mechanisms of cytoadhesion of B. bovis, we panned the parasites with bovine brain microvasculature endothelial cells, which resulted in obtaining several clones with different cytoadherence abilities. The transcriptome analysis of 2 high and 2 low cytoadherent clones revealed that ves1α sequences were diversified, likely resulting from genomic recombination. On the other hand, ves1β sequences were almost identical among these 4 clones. Insertion and expression of ves1α of a clone with high binding into ef-1α locus of a low binding clone increased cytoadherence confirming the role of ves1α suggested by our transcriptome data. Whole genome sequencing of cytoadherent clones revealed active locus of ves1 on chromosome 2. These results suggest that VESA1a proteins encoded by ves1α genes determine the cytoadherence strength of B. bovis and they are in the active site for recombination.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1012583"},"PeriodicalIF":5.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023623","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":"Variable rates of SARS-CoV-2 evolution in chronic infections.","authors":"Ewan W Smith, William L Hamilton, Ben Warne, Elena R Walker, Aminu S Jahun, Myra Hosmillo, Ravindra K Gupta, Ian Goodfellow, Effrossyni Gkrania-Klotsas, M Estée Török, Christopher J R Illingworth","doi":"10.1371/journal.ppat.1013109","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013109","url":null,"abstract":"<p><p>An important feature of the evolution of the SARS-CoV-2 virus has been the emergence of highly mutated novel variants, which are characterised by the gain of multiple mutations relative to viruses circulating in the general global population. Cases of chronic viral infection have been suggested as an explanation for this phenomenon, whereby an extended period of infection, with an increased rate of evolution, creates viruses with substantial genetic novelty. However, measuring a rate of evolution during chronic infection is made more difficult by the potential existence of compartmentalisation in the viral population, whereby the viruses in a host form distinct subpopulations. We here describe and apply a novel statistical method to study within-host virus evolution, identifying the minimum number of subpopulations required to explain sequence data observed from cases of chronic infection, and inferring rates for within-host viral evolution. Across nine cases of chronic SARS-CoV-2 infection in hospitalised patients we find that non-trivial population structure is relatively common, with five cases showing evidence of more than one viral population evolving independently within the host. The detection of non-trivial population structure was more common in severely immunocompromised individuals (p = 0.04, Fisher's Exact Test). We find cases of within-host evolution proceeding significantly faster, and significantly slower, than that of the global SARS-CoV-2 population, and of cases in which viral subpopulations in the same host have statistically distinguishable rates of evolution. Non-trivial population structure was associated with high rates of within-host evolution that were systematically underestimated by a more standard inference method.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013109"},"PeriodicalIF":5.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12061394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046819","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":"HIV-1 cell-to-cell infection of macrophages escapes type I interferon and host restriction factors, and is resistant to antiretroviral drugs.","authors":"Marie Woottum, Sen Yan, Agathe Durringer, Léa Mézière, Lucie Bracq, Mingyu Han, Delphine Ndiaye-Lobry, Julie Chaumeil, Jean-Christophe Pagès, Serge Benichou","doi":"10.1371/journal.ppat.1013130","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013130","url":null,"abstract":"<p><p>HIV-1-infected macrophages participate in viral transmission, dissemination, and establishment of tissue virus reservoirs. Despite counteracting viral proteins (Vif, Vpu, Vpr and Nef), cell-free virus macrophage infection is restricted by host cell factors, including those induced by interferons. Here, we show that these viral proteins and type I interferon do not influence HIV-1 cell-to-cell transfer to macrophages by cell-cell fusion with infected T cells, still leading to the formation of multinucleated giant cells (MGCs). Accordingly, depletion of SERINC5 and APOBEC3G do not alter virus spreading and formation of virus-producing MGCs. We further show that the nuclei derived from infected T cells remains transcriptionally active in MGCs and may explain resistance to restriction factors and antiretroviral drugs. Unexpectedly, we detect viral DNA in myeloid nuclei shortly after the initial fusion with macrophages. Together, these findings unravel how HIV-1 macrophage infection by cell-cell fusion escapes type I interferon and cellular restriction factors independently of the viral auxiliary proteins, while displaying resistance to antiretroviral drugs.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013130"},"PeriodicalIF":5.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023205","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":"Staphylococcus aureus SspA (V8 protease): New skin pathogenesis insights into an old enzyme.","authors":"John C Thorstenson, Alexander R Horswill","doi":"10.1371/journal.ppat.1013048","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013048","url":null,"abstract":"","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013048"},"PeriodicalIF":5.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12021127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053015","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":"Vacuolar sterol β-glucosidase EGCrP2/Sgl1 deficiency in Cryptococcus neoformans: Dysfunctional autophagy and Mincle-dependent immune activation as targets of novel antifungal strategies.","authors":"Takashi Watanabe, Masayoshi Nagai, Yohei Ishibashi, Mio Iwasaki, Masaki Mizoguchi, Masahiro Nagata, Takashi Imai, Koichi Takato, Akihiro Imamura, Yoshimitsu Kakuta, Takamasa Teramoto, Motohiro Tani, Junko Matsuda, Hideharu Ishida, Sho Yamasaki, Nozomu Okino, Makoto Ito","doi":"10.1371/journal.ppat.1013089","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013089","url":null,"abstract":"<p><p>Cryptococcus neoformans (Cn) is a fungal pathogen responsible for cryptococcal meningitis, which accounts for 15% of AIDS-related deaths. Recent studies have shown that the absence of sterol β-glucosidase (EGCrP2, also known as Sgl1) in Cn significantly attenuates its virulence in a mouse infection model. However, the mechanisms underlying this virulence attenuation remain unclear. In this study, we observed a significant increase in dead cells after 3 days of culture of SGL1-deficient Cn (sgl1Δ, KO) at 37°C, compared with wild-type (WT) and SGL1-reconstituted Cn (sgl1Δ::SGL1, RE). qPCR analysis of WT, KO, and RE strains indicated that autophagy-related genes (ATGs) were significantly downregulated in KO strain. Atg8-dependent GFP translocation to the vacuole was significantly delayed in KO strain under starvation conditions. This autophagy dysfunction was identified as the primary cause of the increased cell death observed in KO strain under nitrogen starvation conditions at 37°C. EGCrP2/Sgl1 is predominantly localized in the vacuoles of Cn, and its deletion results in the accumulation of not only ergosterol β-glucoside (EG), as previously reported, but also acylated EGs (AEGs). AEGs were much more potent than EG in activating the C-type lectin receptor Mincle in mice, rats, and humans. AEGs were released from KO strain via extracellular vesicles (EVs). Chemically synthesized 18:1-EG and EVs derived from KO strain, but not WT or RE strains, enhanced cytokine production in murine and human dendritic cells. AEG-dependent cytokine production was markedly reduced in dendritic cells from Mincle-deficient mice, and the number of KO strain in lung tissue from Mincle-deficient mice was substantially higher than wild-type mice on day 3 after infection. Intranasal administration of acylated sitosterol β-glucoside increased Mincle expression and cytokine production and reduced the Cn burden in lung tissue of Cn-infected mice. These findings suggest that autophagy dysfunction in KO strain and the host innate immune response via the AEG-dependent Mincle activation are critical in reducing Cn virulence in mice.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013089"},"PeriodicalIF":5.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12061408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041250","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":"Leveraging microphysiological systems to expedite understanding of host-parasite interactions.","authors":"Maria Zorrinho-Almeida, Jorge de-Carvalho, Maria Bernabeu, Sara Silva Pereira","doi":"10.1371/journal.ppat.1013088","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013088","url":null,"abstract":"<p><p>Microphysiological systems (MPS) replicate the dynamic interactions between cells, tissues, and fluids. They have emerged as transformative tools for biology and have been increasingly applied to host-parasite interactions. Offering a better representation of cellular behavior compared with traditional in vitro models, MPS can facilitate the study of parasite tropism, immune evasion, and life cycle transitions across diverse parasitic diseases. Applications span multiple host tissues and pathogens, leveraging advanced bioengineering and microfabrication techniques to address long-standing knowledge gaps. Here, we review recent advances in MPS applied to parasitic diseases and identify persisting challenges and opportunities for investment. By refining these systems and integrating host multicellular models and parasites, MPS hold vast potential to revolutionize parasitology, enhancing our ability to combat parasitic diseases through deeper mechanistic understanding and targeted interventions.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013088"},"PeriodicalIF":5.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12021206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991647","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}