PLoS Pathogens最新文献

{"title":"A dual interaction between RSV NS1 and MED25 ACID domain reshapes antiviral responses.","authors":"Celia Ait-Mouhoub, Jiawei Dong, Magali Noiray, Jenna Fix, Stepanka Nedvedova, Slim Fourati, Alexis Verger, Jean-Francois Eleouet, Delphyne Descamps, Monika Bajorek, Christina Sizun","doi":"10.1371/journal.ppat.1012930","DOIUrl":"10.1371/journal.ppat.1012930","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV), the most common cause of bronchiolitis and pneumonia in infants, elicits a remarkably weak innate immune response. This is partly due to type I interferon (IFN) antagonism by the non-structural RSV NS1 protein. It was recently suggested that NS1 could modulate host transcription via an interaction with the MED25 subunit of the Mediator complex. Previous work emphasized the role of the NS1 C-terminal helix α3 for recruitment of the MED25 ACID domain, a target of transcription factors (TFs). Here we show that the NS1 α/β core domain binds to MED25 ACID and acts cooperatively with NS1 α3 to achieve nanomolar affinity. The strong interaction is rationalized by the dual NS1 binding site on MED25 ACID predicted by AlphaFold and confirmed by NMR, which overlaps with the two canonical binding interfaces of TF transactivation domains. Single amino acid substitutions in the NS1 α/β domain, notably NS1 E110A, significantly reduced the affinity of NS1 for MED25 ACID, both in vitro and in cellula. These mutations resulted in attenuated replication of recombinant RSV (rRSV-mCherry). They did not significantly upregulate type I or III IFN levels in IFN-competent BEAS-2B cells, contrary to the NS1 α3 deletion. However, in line with attenuated replication, the NS1 E110A mutation enhanced expression of the antiviral interferon-stimulated gene ISG15, and NS1 I54A upregulated ISG15, OAS1A and IFIT1 in IFN-competent cells. In MED25-knockdown cells, rRSV-mCherry replication was further attenuated at a late post-infection timepoint. The difference between WT and NS1 mutant rRSV-mCherry was partially lost, suggesting that the NS1-MED25 ACID complex contributes to controlling antiviral responses at this timepoint. The strong interaction and the extended binding interface between NS1 and MED25 ACID provide evidence for a mechanism, where NS1 blocks access of transcription factors to MED25, and thereby MED25-mediated transcription activation.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1012930"},"PeriodicalIF":4.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12431651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024555","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":"Hnf4α integrates AIF and caspase 3/9 signaling to restrict single and coinfecting pathogens in teleosts.","authors":"Dong Yan, Min Hui Tao, Xiao Man Wu, Jie Zhang, Ming Li, Ming Xian Chang","doi":"10.1371/journal.ppat.1013491","DOIUrl":"10.1371/journal.ppat.1013491","url":null,"abstract":"<p><p>Hepatocyte nuclear factor 4 alpha (Hnf4α), a conserved nuclear receptor central to vertebrate liver development and metabolic regulation, emerges here as a pivotal immune regulator in teleosts against complex infectious threats. While its metabolic roles are well-established, Hnf4α's function in bacterial infection, viral infection, and bacterial-viral coinfection-major challenges in global aquaculture-remained uncharacterized. This study reveals that teleost Hnf4α acts as a dual-functional immune checkpoint, essential for combating Aeromonas salmonicida, grass carp reovirus (GCRV), and their coinfection. In in vivo zebrafish models, hnf4α-deficient larvae showed profound susceptibility, with survival rates reduced by 13.33-40% during infections, whereas gcHnf4α overexpression enhanced larval survival by 17.78-23.33% in single or coinfection scenarios. In vitro analyses in CIK cells demonstrated that gcHnf4α restricts A. salmonicida proliferation and GCRV replication through activation of a mitochondrial apoptotic program. Mechanistically, gcHnf4α forms a nuclear signaling complex with apoptosis-inducing factor (AIF) and caspases 3/9, driving a dual-dependent apoptotic pathway: (1) AIF-mediated caspase-independent nuclear apoptotic processes and (2) caspase 3/9-dependent cytoplasmic apoptotic execution. Confocal microscopy and co-immunoprecipitation validated direct interactions between gcHnf4α and these apoptotic effectors. Pharmacological inhibition of caspases 3/9 or AIF silencing abrogated gcHnf4α's protective effects, while ectopic caspase expression rescued survival deficits in hnf4α-deficient larvae. These findings establish Hnf4α as a conserved molecular nexus linking nuclear receptor signaling to apoptotic immunity, offering a novel strategy for aquacultural disease control. By targeting the AIF-caspase axis, Hnf4α enables efficient pathogen elimination, delineating it as a promising target for developing dual-action immunomodulators.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013491"},"PeriodicalIF":4.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12425335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024543","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":"Cytotoxic CX3CR1+ Vδ1 T cells clonally expand in an interplay of CMV, microbiota, and HIV-1 persistence in people on antiretroviral therapy.","authors":"Nived Collercandy, Camille Vellas, Manon Nayrac, Mary Requena, Thomas Richarme, Anne-Laure Iscache, Justine Latour, Karl Barange, Laurent Alric, Guillaume Martin-Blondel, Matteo Serino, Jacques Izopet, Pierre Delobel","doi":"10.1371/journal.ppat.1013489","DOIUrl":"10.1371/journal.ppat.1013489","url":null,"abstract":"<p><p>Vδ1 γδ T cells are key players in innate and adaptive immunity, particularly at mucosal interfaces such as the gut. An increase in circulating Vδ1 cells has long been observed in people with HIV-1, but remains poorly understood. We performed a comprehensive characterization of Vδ1 T cells in blood and duodenal intra-epithelial lymphocytes, obtained from endoscopic mucosal biopsies of 15 people with HIV-1 on antiretroviral therapy and 15 HIV-seronegative controls, in a substudy of the ANRS EP61 GALT study (NCT02906137). We deciphered the phenotype, functional profile, single-cell transcriptome and repertoire of Vδ1 cells and unraveled their relationships with the possible triggers involved, in particular CMV and microbiota. We also assessed whether Vδ1 T cells may play a role in controlling the HIV-1 reservoir. Vδ1 T cells were mainly terminally differentiated effectors that clonally expanded in the blood with some trafficking with the gut of people with HIV-1. Most expressed CX3CR1 and displayed a highly cytotoxic profile, but low cytokine production, supported by a transcriptomic shift towards enhanced effector lymphocytes. This expansion was associated with CMV status and markers of occult replication, but also with changes in the duodenal and blood-translocated microbiota. Cytotoxic, but not IFN-γ-producing, Vδ1 T cells were negatively associated with cell-associated HIV-1 RNA in both the blood and duodenal compartments. The increase in Vδ1 T cells observed in people with HIV-1 has multiple triggers, particularly CMV and microbiota, and may in turn contribute to the control of the HIV-1 reservoir.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013489"},"PeriodicalIF":4.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12431655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024527","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":"Fexinidazole and Corallopyronin A target Wolbachia-infected sheath cells present in filarial nematodes.","authors":"Laura Chappell, Ricardo Peguero, William R Conner, Sommer Fowler, Brandon S Cooper, Kenneth Pfarr, Achim Hoerauf, Sara Lustigman, Judy Sakanari, William Sullivan","doi":"10.1371/journal.ppat.1012929","DOIUrl":"10.1371/journal.ppat.1012929","url":null,"abstract":"<p><p>The discovery of the endosymbiotic bacteria Wolbachia as an obligate symbiont of. filarial nematodes has led to antibiotic-based treatments for filarial diseases. While lab. and clinical studies have yielded promising results, recent animal studies revealed that Wolbachia levels rebound following treatment with the antibiotic rifampicin. Previous work revealed that a potential source of the bacterial rebound in female worms were dense clusters of Wolbachia in ovarian tissue. The number, size, and density of these Wolbachia clusters were not diminished despite antibiotic treatment. Here we define the cellular characteristics of the Wolbachia clusters in Brugia pahangi (wBp) and identify drugs that target them. We show that the Wolbachia clusters originate from newly formed sheath cells adjacent to the distal tip cell. The dramatically enlarged volume of a Wolbachia-infected sheath cell is strikingly similar to endosymbiont-induced bacteriocytes found in many insect species. Ultrastructural analysis reveals that the clustered Wolbachia present within the sheath cells have a distinct morphology from those present within the oocytes, and that the sheath cell membrane appears to have interdigitations with the adjacent oocyte membrane. This includes membrane-based channels that provide a connection between Wolbachia-infected sheath cells and oocytes. We determined that the Wolbachia within the sheath cells are either quiescent or replicating at a very low rate. Screens of 11 known antibiotics and other drugs revealed that Fexinidazole, Corallopyronin A and Rapamycin reduced the number of Wolbachia clusters infecting sheath cells but only Fexinidazole and Corallopyronin A showed a highly significant difference (p < 0.0001) compared to the control group.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1012929"},"PeriodicalIF":4.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12443271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024549","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":"Activation of PD-1/PD-L1 immune checkpoint by Zika virus.","authors":"Chenxi Wang, Yubin Xie, Weixin Li, Chon Phin Ong, Hao Ding, Shuofeng Yuan, Gong Cheng, Dong-Yan Jin, Zi-Wei Ye","doi":"10.1371/journal.ppat.1013457","DOIUrl":"10.1371/journal.ppat.1013457","url":null,"abstract":"<p><p>Zika virus (ZIKV) has emerged as a rising concern in global health in recent years. The role of PD-1/PD-L1 immune checkpoint in acute ZIKV infection remains to be understood. In this study we demonstrated the activation of PD-1/PD-L1 immune checkpoint by ZIKV. mRNA and protein expression of PD-L1 was boosted by ZIKV not only in SF268 and JEG3 cell lines but also in human dendritic cells. PD-1 expression was more abundant on CD8+ T cells in ZIKV-infected mice. Elevated PD-L1 expression was also observed in the brain, testis and spleen of ZIKV-infected A129 mice. Blocking PD-L1 effectively inhibited ZIKV infection, reducing viral loads in all tissues. In addition, anti-PD-L1 antibody treatment further increased virus-specific CD8+ T cells, KLRG+ CD8+ T cells, and effector memory CD8+ T cells. PD-L1 blockade also induced interferon γ, granzyme B, and interleukin 2 expression in antigen-specific CD8+ T cells, consistent with activation of these cells. Mechanistically, the induction of PD-L1 expression might be ascribed to viral NS4B protein and its interaction with GRP78. Our findings suggest that targeting the PD-1/PD-L1 pathway could have antiviral effect against ZIKV.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013457"},"PeriodicalIF":4.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12431654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024520","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":"Discovery and mechanistic insights of dibenzoylmethane as a broad spectrum inhibitor of coronavirus.","authors":"Yuan Sun, Xiaoyang Shu, Lu Chen, Weijuan Shang, Yumin Zhang, Gengfu Xiao, Leike Zhang","doi":"10.1371/journal.ppat.1013492","DOIUrl":"10.1371/journal.ppat.1013492","url":null,"abstract":"<p><p>Coronavirus, a large family of positive-sense RNA viruses, are responsible for both mild and severe respiratory illnesses, ranging from the common cold to life-threatening conditions. Despite significant advances in vaccine and antiviral development, the high mutability of human coronaviruses (HCoVs), such as SARS-CoV-2, presents a major challenge in treating these infections. Effective, broad-spectrum antiviral drugs are urgently needed to address both current and future HCoV outbreaks. Here, we conducted high-throughput screening of a natural product library containing 3407 compounds to identify potential antiviral agents against HCoV-OC43 and HCoV-229E. We identified several natural products with inhibitory effects on HCoV-229E, HCoV-OC43, and the SARS-CoV-2 variants Delta (B.1.617.2) and Omicron (BA.5) in vitro without evident cytotoxicity. Among these, dibenzoylmethane (DBM) not only demonstrated broad-spectrum anticoronavirus activity in vitro but also effectively inhibited HCoV-OC43 replication in a BALB/c mouse model. Pharmacokinetic analysis revealed that DBM, when administered orally, maintained effective concentrations in the blood over an extended period, suggesting its suitability for oral administration. Mechanistically, DBM was found to regulate caspase-6, a host factor that suppresses interferon signalling and promotes HCoV replication. These findings highlight DBM as a promising candidate for the development of therapeutics targeting HCoVs, offering potential for treating infections by both established and emerging HCoVs.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013492"},"PeriodicalIF":4.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12431657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024567","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":"N460S in PB2 and I163T in nucleoprotein synergistically enhance the viral replication and pathogenicity of influenza B virus.","authors":"Yang Wang, Yu Gao, Tianxin Ma, Yuting Ye, Chenyang Cao, Binqian Zou, Sulan Ye, Qingsheng Huang, Chunguang Yang, Shengfeng Li, Lixi Liang, Hongxuan Zhou, Zhiqi Zeng, Zifeng Yang, Weiqi Pan","doi":"10.1371/journal.ppat.1013463","DOIUrl":"10.1371/journal.ppat.1013463","url":null,"abstract":"<p><p>Influenza B viruses (IBVs), though often overshadowed by influenza A viruses (IAVs), remain a significant global public health concern, particularly during seasons when they predominate. However, the molecular mechanisms underlying IBV pathogenicity remain largely unknown. In this study, we identified two amino acid substitutions, PB2-N460S and NP-I163T, from IBV clinical isolates with distinct replication and pathogenicity profiles. Using reverse genetics, we generated recombinant IBV viruses to evaluate the impact of these substitutions. In vitro and in vivo infections revealed that viral replication and pathogenicity were not significantly affected by either substitution alone but were substantially enhanced when both substitutions occurred together. Lung transcriptomics in mice infected with virus containing PB2-N460S/NP-I163T substitutions showed heightened immune activation. This was characterized by upregulated transcription of antiviral and immune-related genes, contributing to excessive inflammation and severe disease outcomes. Mechanistic investigations demonstrated that each substitution independently increased protein expression and strengthened PB2-NP interactions. However, only the combined presence of PB2-N460S and NP-I163T significantly enhanced polymerase activity. Structural modeling indicated that PB2-460 residue is positioned at the PB2-NP interface, while NP-163 site resides distally, suggesting an indirect functional interplay. These findings provide new insights into the molecular determinants of IBV pathogenesis, highlighting the synergistic effect of PB2-N460S and NP-I163T in enhancing viral fitness and worsening disease outcomes.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013463"},"PeriodicalIF":4.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12431660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024615","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":"Identification and antiviral mechanism of a novel chicken-derived interferon-related antiviral protein targeting PRDX1.","authors":"Jing Chen, Peiheng Li, Letian Li, Ju Li, Yuhang Jiang, Wancheng Zou, Pengfei Hao, Zihan Gao, Jiayi Hao, Xiaoshuang Shi, Dongliang Fei, Mingxiao Ma, Guoqing Wang, Chang Li","doi":"10.1371/journal.ppat.1013495","DOIUrl":"10.1371/journal.ppat.1013495","url":null,"abstract":"<p><p>In this study, we identified a new chicken-specific protein, named chicken interferon-related antiviral protein (chIRAP) after sequence analysis and comparison, which inhibited the proliferation of various viruses including influenza A virus (IAV) and Newcastle Disease Virus (NDV) in vitro, and chicken embryos with high expression of chIRAP reduced IAV infection. Mass spectrometry analysis of chIRAP interacting proteins and screening of interacting proteins affecting the function of chIRAP revealed that the deletion of endogenous chicken peroxiredoxin 1 (chPRDX1) significantly reduced the antiviral effect of chIRAP. In order to clarify the functional site of chPRDX1 affecting the antiviral effect of chIRAP, we constructed the point mutants of chPRDX1 based on the results of molecular docking (D79A, T90A, K93A, Q94A, R110A, R123A), and screened the sites affecting the antiviral effects of chIRAP by knockdown of endogenous chPRDX1 combined with the overexpression mutant strategy, the results showed that the mutations in the sites affected the antiviral effects of chIRAP to different degrees, with D79A being the most significant, and the D79A mutation of chPRDX1 reduces the ability of chPRDX1 to regulate reactive oxygen species (ROS). chIRAP may exert antiviral effects by regulating the intracellular ROS balance at the D79 site of chPRDX1. In conclusion, we identified a novel chicken-derived antiviral protein, clarified its antiviral effects and preliminarily explored its mechanism of action, which provides a new tool and option for the prevention and treatment of avian-origin viral diseases, especially avian-origin related zoonotic diseases.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013495"},"PeriodicalIF":4.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12431653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024533","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":"Receptor transporter protein 4 (RTP4)-mediated repression of hepatitis C virus replication in mouse cells.","authors":"Michael P Schwoerer, Sebastian Carver, Aaron E Lin, Jianche Liu, Thomas R Cafiero, Keith A Berggren, Serene Dhawan, Saori Suzuki, Brigitte Heller, Celeste Rodriguez, Aoife K O'Connell, Hans P Gertje, Nicholas A Crossland, Alexander Ploss","doi":"10.1371/journal.ppat.1013412","DOIUrl":"10.1371/journal.ppat.1013412","url":null,"abstract":"<p><p>Hepatitis C virus (HCV) exhibits a narrow species tropism, causing robust infections only in humans and experimentally inoculated chimpanzees. While many host factors and restriction factors are known, many more likely remain unknown, which has limited the development of mouse or other small animal models for HCV. One putative restriction factor, the black flying fox orthologue of receptor transporter protein 4 (RTP4), was previously shown to potently inhibit viral genome replication of several ER-replicating RNA viruses. Since the murine but not the human ortholog is a potent inhibitor of HCV, we aimed to analyze the potential role for RTP4 in restricting HCV replication in mice. We demonstrated that mouse RTP4 (mmRTP4) functions as a dominant inhibitor of HCV infection. Via interspecies domain-mapping, we identified the zinc-finger domain (ZFD) of murine RTP4 as essential for inhibiting HCV, consistent with prior work. Introducing mmRTP4 into HCV-infected Huh7 cells profoundly reduced HCV NS5A protein production and virion release, demonstrating that mmRTP4 can also disrupt already established HCV replication complexes. This inhibition of HCV was not driven by induction of interferon-stimulated genes based on bulk RNA-seq, suggesting that mmRTP4 might directly act on HCV replication. Indeed, by in situ proximity ligation, we found that mmRTP4 directly associates with the HCV NS5A protein significantly more than human RTP4 during infection. However, disrupting RTP4 expression in mice expressing humanized alleles of CD81 and occludin (OCLN) - the species specific cellular factors mediating HCV uptake - did not increase permissiveness irrespective of the immunocompetence of the mice. Collectively, our work provides detailed insights into the role of RTP4 in contributing to HCV's narrow host range and will inform downstream development of a more comprehensive small-animal model for this important pathogen.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013412"},"PeriodicalIF":4.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12431671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024552","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":"Immune signatures of SARS-CoV-2 infection resolution in human lung tissues.","authors":"Devin Kenney, Aoife K O'Connell, Anna E Tseng, Jacquelyn Turcinovic, Maegan L Sheehan, Adam D Nitido, Paige Montanaro, Hans P Gertje, Maria Ericsson, John H Connor, Vladimir Vrbanac, Nicholas A Crossland, Christelle Harly, Alejandro B Balazs, Florian Douam","doi":"10.1371/journal.ppat.1013469","DOIUrl":"10.1371/journal.ppat.1013469","url":null,"abstract":"<p><p>While human autopsy samples have provided insights into pulmonary immune mechanisms associated with severe viral respiratory diseases, the mechanisms that contribute to a clinically favorable resolution of viral respiratory infections remain unclear due to the lack of proper experimental systems. Using mice co-engrafted with a genetically matched human immune system and fetal lung xenograft (fLX), we mapped the immunological events defining successful resolution of SARS-CoV-2 infection in human lung tissues. Viral infection is rapidly cleared from fLX following a peak of viral replication, histopathological manifestations of lung disease and loss of AT2 program, as reported in human COVID-19 patients. Infection resolution is associated with the activation of a limited number of hematopoietic subsets, including inflammatory monocytes and CD3-expressing macrophage-like cells, which are highly enriched in viral RNA and dissipate upon infection resolution. Specific human fibroblast and endothelial subsets also elicit robust antiviral and monocyte chemotaxis signatures, respectively. Notably, systemic depletion of human CD4 + cells, but not CD3 + cells, significantly abrogates infection resolution in fLX and induces persistent infection, supporting the dominant role of peripheral CD4 + monocytes over T-cells in the resolution of acute SARS-CoV-2 infection. Collectively, our findings unravel a comprehensive picture of the immunological events defining effective resolution of SARS-CoV-2 infection in human lung tissues, revealing markedly divergent immunological trajectories between resolving and fatal COVID-19 cases.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013469"},"PeriodicalIF":4.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12425302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024612","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}