PLoS Pathogens最新文献

{"title":"The F1148 hydrophobic lock: A critical determinant of SARS-CoV-2 spike protein-mediated membrane fusion via the 3H/CH cavity.","authors":"Fuzhi Lei, Yahan Lei, Zhenghong Yuan, Zhigang Yi","doi":"10.1371/journal.ppat.1013526","DOIUrl":"10.1371/journal.ppat.1013526","url":null,"abstract":"<p><p>The S2 subunit of the coronavirus Spike protein undergoes extensive conformational refolding to drive membrane fusion during viral entry. Although the HR1/HR2 six-helix bundle (6-HB) is recognized as the core mediator of fusion, the molecular driving force governing its formation remains poorly elucidated. Here, through systematic mutagenesis of the AlphaFold-predicted stem helix (SH) region in S2, followed by analysis of the resulting SC2-VLP entry phenotypes, we identified key amino acid residues within conserved helices that are present in both prefusion and postfusion Spike conformations. These elements, which we term postfusion-preserved helices (PFPHs), were found to be critical for SC2-VLP entry. Structural analysis revealed a \"hydrolock\" interaction between F1148 in PFPH-1 and a conserved cavity formed by 3H (I742, C749)/CH (I993, L996, I997). Deep mutational scanning demonstrated that only hydrophobic residues at F1148 were functionally viable and essential for membrane fusion, underscoring the critical role of a hydrophobic lock (\"hydrolock\") interaction between F1148 and the 3H/CH cavity in membrane fusion. Furthermore, HA-replacement mutagenesis and anti-HA neutralization assays showed that significant neutralization activity was restricted to HA insertions proximal to PFPH-1, selectively inhibiting membrane fusion without affecting receptor binding. Notably, the 3H/CH cavity remains structurally stable across Spike conformations, being sequentially occupied by prefusion-L977, intermediate-F782, and postfusion-F1148. We propose a model wherein hydrolock interactions drive S2 refolding and fusion by displacing intermediate interactions. This study provides mechanistic insights into Spike dynamics and highlights hydrolock interactions as a promising target for broad-spectrum antiviral strategies.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013526"},"PeriodicalIF":4.9,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092676","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 PGRPLC1/Rel2-F axis controls Anopheles gambiae resistance to systemic infections with Gram-positive bacteria containing Lys-type peptidoglycan.","authors":"Amani Audi, Suheir Zeineddine, Sana Jaber, Mike A Osta","doi":"10.1371/journal.ppat.1013527","DOIUrl":"10.1371/journal.ppat.1013527","url":null,"abstract":"<p><p>In the Afrotropical malaria vector Anopheles gambiae s.l., the Imd pathway plays pleiotropic roles in immunity, including resistance to malaria parasites, that are mediated by its NF-κB transcription factor Rel2. Rel2 exists as a full-length form (Rel2-F) containing the Rel-homology domain (RHD) and the C-terminal inhibitory ankyrin (Ank) and death domains (DD), and a shorter alternatively spliced form (Rel2-S) proposed to encode a constitutively active protein containing only the RHD. Despite its important roles in immunity, there are still multiple uncertainties concerning the identity and function of key components of the pathway as well as its overall contribution to mosquito resistance to systemic bacterial infections. Here, we show that Rel2 is critical for limiting the burden of Gram-negative and Gram-positive bacterial proliferation in An. gambiae s.s. after systemic infections and this function is attributed to the endoproteolytic activation of Rel2-F in the fat body but not to Rel2-S. Interestingly, while Rel2-F activation in the fat body regulates Cecropin 1 and Defensin 1 expression, its activation in the midgut after oral infections is dispensable for their regulation. We provide direct evidence that PGRPLC1 is necessary and sufficient for Rel2-F activation in the fat body in response to infections with Gram-positive bacteria containing Lysine-type peptidoglycan, however sensing of Gram-negative bacteria and Gram-positive bacilli containing DAP-type peptidoglycan is more complex and may be mediated by various PGRPLC isoforms, indicating that the mosquito Imd pathway integrates distinct receptor modules to sense Gram-positive and Gram-negative bacterial infections.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013527"},"PeriodicalIF":4.9,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092631","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":"Pathogen-induced damage in Drosophila: Uncoupling disease tolerance from resistance.","authors":"Priscilla A Akyaw, Tânia F Paulo, Elvira Lafuente, Élio Sucena","doi":"10.1371/journal.ppat.1013482","DOIUrl":"10.1371/journal.ppat.1013482","url":null,"abstract":"<p><p>Immune response against infections can be divided into mechanisms of resistance that ensure active pathogen elimination, and mechanisms of disease tolerance, which include processes that return the host to physiological homeostasis without direct control of pathogen load. Studies on host immune response to infection have targeted mechanisms of resistance, and consequently, these are now well-described in both vertebrates and invertebrates. By comparison, the mechanistic basis of disease tolerance is poorly understood. This is in part because both processes interact and can be difficult to disentangle under an infection scenario. Using the insect model Drosophila melanogaster exposed to its natural entomopathogen, Pseudomonas entomophila, we aimed to tease apart mechanisms of disease tolerance from those of resistance. To this end, we reasoned that the response to oral exposure to heat-killed entomopathogenic bacteria, whilst initially triggering both resistance and disease tolerance mechanisms, would be resolved mainly by disease tolerance alone. Using this method, we observe that oral exposure to heat-killed P. entomophila causes mortality and reduced fecundity in D. melanogaster. We confirm that this reduction in fitness-related traits depends on the duration of the exposure, is sexually dimorphic, and is dependent on the virulence of the bacterium. We also found the microbiota to play a role, with its presence exacerbating the deleterious effect on host survival. In addition, we show that the Imd pathway, but not effector genes, is involved in the process of surviving exposure to HK bacteria. This experimental framework, which may be extended to other systems, can be instrumental towards an understanding of the molecular, genetic, and physiological basis of disease tolerance and its interactions with resistance mechanisms.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013482"},"PeriodicalIF":4.9,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12463329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092613","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 association of class II HLA alleles with tuberculosis-associated immune reconstitution inflammatory syndrome.","authors":"Phuti Choshi, Sarah Pedretti, Tafadzwa Chimbetete, Rama Gangula, Muki Shey, Cari Stek, Rachel P J Lai, Robert Wilkinson, Graeme Meintjes, Elizabeth Phillips, Jonny Peter","doi":"10.1371/journal.ppat.1013497","DOIUrl":"10.1371/journal.ppat.1013497","url":null,"abstract":"<p><p>Genetic associations within the human leukocyte antigen (HLA) gene complex and linked genes in TB-IRIS outcomes remains population specific and not well understood. Here, we conducted a study including well characterised HIV-TB coinfected patients with (n = 86) and without (n = 124) TB-IRIS from the randomized, double-blind, prophylactic prednisone trial (PredART study) with HLA, ERAP and KIR genotyping data. We confirmed the association of TB-IRIS with lower CD4 counts pre-ART initiation. We identified nine classical class I and II HLA alleles protective against TB-IRIS, while four alleles were linked to increased risk. Associations ranged from strongly protective (HLA-DQB1*05:01, OR: 0.07, 95%CI: 0.02-0.28, Pc < 0.001) to strongly risk associated (notably DRB1*01:02, OR: 5.92, 95%CI: 1.36-26.7, Pc = 0.028), with conflicting signals at the HLA-DRB1 locus. Conditional regression analysis revealed that residue E71 at the polymorphic position 71 within the HLA-DRB1 peptide-binding groove was critical, and grouping of HLA-DRB1 alleles by the residue at position 71 corresponded with differential TB-IRIS association. In conclusion, this study identifies population-specific genetic factors influencing TB-IRIS susceptibility and highlights a potential mechanistic role for specific HLA-DRB1 residues in modulating immune responses during ART.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013497"},"PeriodicalIF":4.9,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12510654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092610","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 single amino acid variant in the variable region I of AAV capsid confers liver detargeting.","authors":"Ruxiao Xing, Mengyao Xu, Darcy Reil, April Destefano, Mengtian Cui, Nan Liu, Jialing Liang, Guangchao Xu, Li Luo, Meiyu Xu, Fang Zhang, Phillip W L Tai, Yuquan Wei, Alisha M Gruntman, Terence R Flotte, Guangping Gao, Dan Wang","doi":"10.1371/journal.ppat.1013533","DOIUrl":"10.1371/journal.ppat.1013533","url":null,"abstract":"<p><p>AAV capsid serotypes isolated from nature have been widely used in gene delivery and gene therapy. Recently, more than 1,000 distinct AAV capsids were identified from human clinical samples by high-throughput, long-read DNA sequencing. In this study, we tap into this broad natural biodiversity of AAV capsids to develop liver-tropic AAV capsids. We initially screened a subset of variants derived from AAV8 (n = 159) for packaging efficiency. The high-yielding variants were subjected to a barcoded vector library screen in mice and ferrets for their ability to mediate liver gene transfer. Although no variant surpassed AAV8 for liver targeting, several exhibited a liver detargeting phenotype. Among these, we focused on the N271D variant (AAV8 VP1 numbering), located in the variable region I (VR-1), which has been previously implicated in influencing liver tropism. The liver detargeting phenotype of AAV8.N271D was confirmed by single vector administration in mice. Additionally, we grafted the N271D variant onto AAV9 and MyoAAV capsids (N270D by AAV9 VP1 numbering). The AAV9.N270D and MyoAAV.N270D vectors showed a similar liver-detargeting phenotype, although muscle targeting was moderately reduced. Although we did not identify any capsid variants that outperform AAV8 in liver transduction, this study reinforces the important role of VR-1 in modulating liver tropism and highlights the potential of engineering VR-1 residues to reduce liver gene transfer and associated toxicity observed in several gene therapy studies.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013533"},"PeriodicalIF":4.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082314","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 non-canonical activation of the host's ESCRT machinery is required for the scission of parasitophorous vacuoles and the replication of Leishmania donovani.","authors":"Javier Rosero, Peter E Kima","doi":"10.1371/journal.ppat.1013513","DOIUrl":"10.1371/journal.ppat.1013513","url":null,"abstract":"<p><p>Leishmania donovani (Ld) is the causative agent of visceral leishmaniasis, which results in death if not treated. In mammalian cells, Ld live in vacuolar compartments called Leishmania parasitophorous vacuoles (LdLPVs) that enigmatically divide following parasite replication. We evaluated the role of the endosomal sorting complex required for transport (ESCRT) machinery in the scission of LdLPVs. We found that ESCRT components are constitutively recruited to LdLPVs. We propose that this recruitment depends on the expression of PI(3,4)P2 on LdLPVs. The knockdown (KD) of upstream components of the ESCRT machinery revealed that ALIX, but not TSG101 or VPS28, led to a significant reduction in the parasite burden in infected cultures. Interestingly, LdLPVs in ALIXKDs were more distended and harbored more than 2 parasites. Incorporation of BrdU into Leishmania in THP-1 macrophages revealed that parasite replication was inhibited in ALIXKD due to defective LdLPV scission. These findings establish that non-canonical activation of the ESCRT machinery is required for Leishmania to replicate within macrophages.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013513"},"PeriodicalIF":4.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076455","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":"Differential tissue tropism and transmission efficiency of two dominant influenza D clades with overlapping but distinct receptor binding fine specificities in ferrets.","authors":"Tirth Uprety, Chithra C Sreenivasan, Jieshi Yu, Miaoyun Zhao, Runxia Liu, Hai Yu, Ahsan Naveed, Lianne G Eertink, Shalini Soni, Rebecca E Ruby, Xi Chen, Radhey S Kaushik, Zizhang Sheng, Qingsheng Li, Dan Wang, Feng Li","doi":"10.1371/journal.ppat.1013493","DOIUrl":"10.1371/journal.ppat.1013493","url":null,"abstract":"<p><p>Influenza D virus (IDV) utilizes bovines as a primary reservoir causing periodical spillover to pigs and other hosts. In this study, we utilized ferrets to study IDV with a focus on the role of the Hemagglutinin-Esterase-Fusion (HEF) protein in the replication, tissue tropism, and transmission of two dominant clades of IDV- swine D/OK, and bovine D/660. In addition to swine D/OK, we rescued a chimeric virus (D/OK660HEF) expressing the bovine D/660 HEF using reverse genetic system. Two isogenic IDVs differing only in the HEF protein were characterized in ferrets with respect to viral shedding, tissue tropism, transmission, and pathogenesis. Ferrets intranasally infected with D/OK and D/OK660HEF showed similar levels of viral shedding but exhibited slight differences in transmission efficiency to contact sentinel ferrets. Specifically, D/OK replicated mostly in the upper respiratory tract and transmitted to 2/3 naive ferrets, while D/OK660HEF replicated in both upper and lower respiratory tract (trachea) but transmitted only to 1/3 naive ferrets. Both direct inoculated and contact sentinel ferrets seroconverted at 14 days post-infection, which indicated an association with viral replication fitness and transmission efficiency. Distinct receptor fine specificities plus six amino acid mutations in the receptor binding domain of the HEF protein between swine D/OK and bovine D/660 viruses may explain the different tissue tropism and transmission efficiency observed between these two viruses. Furthermore, while no detectable virus titers were observed in the lungs and intestines of ferrets, fluorescent RNAscope probe-based in-situ hybridization assay detected viral RNAs in these tissues. Finally, deep-sequencing revealed ferret-adapted mutations in PB1, PB2, and M segments that have not appeared in natural IDV isolates from bovines or pigs which need further characterization. Taken together, results of this study demonstrate that IDV is optimized for replication and spread in mammals and subtle mutations in HEF protein may affect viral tropism and transmission efficiency.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013493"},"PeriodicalIF":4.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070994","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":"Single-round infectious rotaviruses with deletions of VP7 or VP4 genes, based on SA11 and WC3 strain backbones, and their potential use as viral vectors.","authors":"Tomohiro Kotaki, Yuta Kanai, Megumi Onishi, Yusuke Sakai, Daisuke Motooka, Zelin Chen, Yasutaka Enoki, Sayuri Komatsu, Katsuhisa Hirai, Shohei Minami, Takahiro Kawagishi, Hiroshi Ushijima, Takeshi Kobayashi","doi":"10.1371/journal.ppat.1013484","DOIUrl":"10.1371/journal.ppat.1013484","url":null,"abstract":"<p><p>Single-round infectious rotavirus, which lacks a gene essential for virion assembly, serves not only as a safe and effective rotavirus vaccine but also as an orally-administrable viral vector vaccine that induces mucosal immunity. Previously, we generated a single-round infectious rotavirus by partially deleting the viral VP6 gene, and demonstrated its potential as a promising vaccine platform. However, this system has several limitations; namely, low viral protein expression levels and safety concerns. Here, we addressed these challenges by introducing large deletions into the VP7 or VP4 genes, which are dispensable for viral protein expression but essential for virion assembly. These VP7- or VP4-defective viruses exhibited markedly higher protein expression in wild-type MA104 cells than the previously developed VP6-defective virus. In addition, the large deletions reduce the risk of viral reversion, thereby increasing both efficacy and safety. In a mouse model, these viruses induced neutralizing antibodies at levels comparable with those elicited by wild-type rotavirus, indicating their potential as rotavirus vaccines. Moreover, a VP4-defective rotavirus harboring a heterologous gene achieved high expression of heterologous proteins, warranting its application as a viral vector vaccine. To further increase safety, we established a reverse genetics system for the bovine rotavirus WC3 strain, a parental strain of the licensed live attenuated rotavirus vaccine, and successfully generated a single-round VP4-defective rotavirus based on the WC3 backbone. Taken together, these optimizations facilitate development of safe and effective single-round infectious rotavirus platforms suitable for human use.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013484"},"PeriodicalIF":4.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071040","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":"Proximity labelling reveals VPS13C as a regulator of Salmonella-containing vacuole fission.","authors":"Anna K Waldmann, Dustin A Ammendolia, Andrew M Sydor, Ren Li, Jonathan St-Germain, Brian Raught, John H Brumell","doi":"10.1371/journal.ppat.1013507","DOIUrl":"10.1371/journal.ppat.1013507","url":null,"abstract":"<p><p>Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing vacuole (SCV). The molecular composition and regulatory mechanisms governing SCV dynamics remain incompletely understood. In this study, we employed proximity-dependent biotin identification (BioID) to analyze the SCV proteome during infection. For this, we targeted the UltraID biotin ligase to the SCV by fusing it to a type 3 secreted effector. We demonstrate that the bacteria express and translocate the effector-UltraID fusion protein directly into host cells for labeling of the cytosolic face of the SCV surface. Proteomic analysis of biotinylated proteins revealed previously undescribed proteins associated with the SCV, including regulators of vesicular trafficking, cellular metabolism and lipid transport. Among these, VPS13C, a lipid transporter and membrane contact site protein, was identified as a critical regulator of SCV morphology and fission. Functional studies revealed that VPS13C also promotes ER-SCV contact formation, controls SCV positioning in host cells, and facilitates cell-to-cell spread by the bacteria. Together, our findings highlight the utility of BioID as a tool to study host-pathogen interactions in the context of infection and characterize VPS13C as a novel modulator of the intracellular life cycle of S. Typhimurium.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013507"},"PeriodicalIF":4.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071058","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":"Chimeric PRR T-cell-engager targeting cell surface β-1,3-glucan for invasive candidiasis.","authors":"Yu Fang Sun, Shi Yu Guo, Si Qi Wang, Rui Tong Li, Xi Ran Qiu, Xing Chen Dong, Shuang Liu, Hui Shen, Mao Mao An","doi":"10.1371/journal.ppat.1013508","DOIUrl":"10.1371/journal.ppat.1013508","url":null,"abstract":"<p><p>Invasive candidiasis, primarily caused by Candida albicans, represents the most common fungal disease among hospitalized patients and poses a significant threat to human health. Intrinsic or acquired immunosuppression serves as a critical risk factor predisposing individuals to this disease, while simultaneously reducing the efficacy of conventional antifungal therapies and worsening clinical outcomes. Given the central role of immune dysfunction in the pathogenesis of invasive candidiasis, immunotherapeutic strategies hold substantial promise. We targeted dectin-1, the primary pattern recognition receptor for β-1,3-glucan, by engineering XJ104, a bispecific T-cell engager that fuses dectin-1 to the light chains of an anti-CD3 monoclonal antibody. This construct is designed to bridge Candida β-1,3-glucan with CD3 on T cells, thereby inducing anti-Candida immunity. Our results demonstrate that XJ104 exhibits high specificity for β-1,3-glucan and activates effector cells in a Candida-dependent manner in vitro. In murine models, XJ104 enhances Th1 and Th17 responses and confers significant protection against both C. albicans and non-albicans infections. Crucially, CD3+ T-cell depletion and cytokine neutralization abolished this protection, confirming the T-cell-dependent protective efficacy of XJ104. These results establish that enhancing the endogenous T-cell function represents an effective strategy against invasive candidiasis. In conclusion, our study presents a novel therapeutic approach that bridges T cells and Candida pathogens, promoting robust Candida-specific immunity and controlling invasive infections caused by Candida spp. These findings underscore the potential of XJ104 as a clinically promising immunotherapy for the treatment of invasive candidiasis.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013508"},"PeriodicalIF":4.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12478890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070939","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}