Journal of Clinical Investigation最新文献

{"title":"Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors.","authors":"Silvana Bazua-Valenti, Matthew R Brown, Jason Zavras, Magdalena Riedl Khursigara, Elizabeth Grinkevich, Eriene-Heidi Sidhom, Keith H Keller, Matthew Racette, Moran Dvela-Levitt, Catarina Quintanova, Hasan Demirci, Sebastian Sewerin, Alissa C Goss, John Lin, Hyery Yoo, Alvaro S Vaca Jacome, Malvina Papanastasiou, Namrata Udeshi, Steven A Carr, Nina Himmerkus, Markus Bleich, Kerim Mutig, Sebastian Bachmann, Jan Halbritter, Stanislav Kmoch, Martina Živná, Kendrah Kidd, Anthony J Bleyer, Astrid Weins, Seth L Alper, Jillian L Shaw, Maria Kost-Alimova, Juan Lorenzo B Pablo, Anna Greka","doi":"10.1172/JCI180347","DOIUrl":"10.1172/JCI180347","url":null,"abstract":"<p><p>The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive. Here, we report that transmembrane Emp24 protein transport domain-containing (TMED) cargo receptors TMED2, TMED9, and TMED10 bind UMOD and regulate its trafficking along the secretory pathway. Pharmacological targeting of TMEDs in cells, in human kidney organoids derived from patients with ADTKD-UMOD, and in mutant-UMOD-knockin mice reduced intracellular accumulation of mutant UMOD and restored trafficking and localization of UMOD to the apical plasma membrane. In vivo, the TMED-targeted small molecule also mitigated ER stress and markers of kidney damage and fibrosis. Our work reveals TMED-targeting small molecules as a promising therapeutic strategy for kidney proteinopathies.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836526","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":"Pathobiont-driven antibody sialylation through IL-10 undermines vaccination.","authors":"Chih-Ming Tsai, Irshad A Hajam, J R Caldera, Austin Wt Chiang, Cesia Gonzalez, Xin Du, Biswa Choudhruy, Haining Li, Emi Suzuki, Fatemeh Askarian, Ty'Tianna Clark, Brian Lin, Igor H Wierzbicki, Angelica M Riestra, Douglas J Conrad, David J Gonzalez, Victor Nizet, Nathan E Lewis, George Y Liu","doi":"10.1172/JCI179563","DOIUrl":"10.1172/JCI179563","url":null,"abstract":"<p><p>The pathobiont Staphylococcus aureus (Sa) induces nonprotective antibody imprints that underlie ineffective staphylococcal vaccination. However, the mechanism by which Sa modifies antibody activity is not clear. Herein, we demonstrate that IL-10 is the decisive factor that abrogates antibody protection in mice. Sa-induced B10 cells drive antigen-specific vaccine suppression that affects both recalled and de novo developed B cells. Released IL-10 promotes STAT3 binding upstream of the gene encoding sialyltransferase ST3gal4 and increases its expression by B cells, leading to hyper-α2,3sialylation of antibodies and loss of protective activity. IL-10 enhances α2,3sialylation on cell-wall-associated IsdB, IsdA, and MntC antibodies along with suppression of the respective Sa vaccines. Consistent with mouse findings, human anti-Sa antibodies as well as anti-pseudomonal antibodies from cystic fibrosis subjects (high IL-10) are hypersialylated, compared with anti-Streptococcus pyogenes and pseudomonal antibodies from normal individuals. Overall, we demonstrate a pathobiont-centric mechanism that modulates antibody glycosylation through IL-10, leading to loss of staphylococcal vaccine efficacy.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836554","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":"Interleukin 10 drives Staphylococcus aureus imprinting and vaccine failure in murine models via antibody glycosylation.","authors":"Victor J Torres","doi":"10.1172/JCI187055","DOIUrl":"10.1172/JCI187055","url":null,"abstract":"<p><p>Despite many attempts, there is currently no approved vaccine to prevent Staphylococcus aureus infections. Preclinical vaccination models have failed to predict vaccine efficacy in humans as S. aureus exposure in humans imprints an immune response that is lacking in naive animals. In this issue of the JCI, Tsai and colleagues identify the cytokine IL-10 as the driver of humoral imprinting by S. aureus. Upon vaccination, S. aureus-experienced animals produced copious levels of IL-10, resulting in the hyper-α2,3 sialylation of antibodies, which interfered with the phagocytic-promoting properties of the vaccine-elicited anti-S. aureus antibodies. These findings correlate with the observation that hyperproduction of IL-10 in humans also induces hyper-α2,3 sialylation of antibodies and provide a possible mechanism for previous vaccine failures.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 24","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836551","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":"Senescence of endothelial cells increases susceptibility to Kaposi's sarcoma-associated herpesvirus infection via CD109-mediated viral entry.","authors":"Myung-Ju Lee, Jun-Hee Yeon, Jisu Lee, Yun Hee Kang, Beom Seok Park, Joo Hee Park, Sung-Ho Yun, Dagmar Wirth, Seung-Min Yoo, Changhoon Park, Shou-Jiang Gao, Myung-Shin Lee","doi":"10.1172/JCI183561","DOIUrl":"https://doi.org/10.1172/JCI183561","url":null,"abstract":"<p><p>The aging process is characterized by cellular functional decline and increased susceptibility to infections. Understanding the association between virus infection and aging is crucial for developing effective strategies against viral infections in older individuals. However, the relationship between Kaposi's sarcoma-associated herpesvirus (KSHV) infection, a cause of Kaposi's sarcoma prevalent among the elderly without HIV infection, and cellular senescence remains enigmatic. This study uncovers a fascinating link between cellular senescence and enhanced KSHV infectivity in human endothelial cells. Through a comprehensive proteomic analysis, we identified caveolin-1 and CD109 as novel host factors significantly upregulated in senescent cells that promote KSHV infection. Remarkably, CRISPR-Cas9-mediated knockout of these factors reduced KSHV binding and entry, leading to decreased viral infectivity. Furthermore, surface plasmon resonance analysis and confocal microscopy revealed a direct interaction between KSHV virions and CD109 on the cell surface during entry, with recombinant CD109 protein exhibiting an intriguing ability to inhibit infection by blocking virion binding. These findings uncover a previously unrecognized role of cellular senescence in enhancing KSHV infection through upregulation of specific host factors and provide novel insights into the complex interplay between aging and viral pathogenesis.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812566","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":"Clinical tolerance but no protective efficacy in a placebo-controlled trial of repeated controlled schistosome infection.","authors":"Jan Pieter R Koopman, Emma L Houlder, Jacqueline J Janse, Olivia Ac Lamers, Geert Vt Roozen, Jeroen C Sijtsma, Miriam Casacuberta-Partal, Stan T Hilt, M Y Eileen C van der Stoep, Inge M van Amerongen-Westra, Eric At Brienen, Linda J Wammes, Lisette van Lieshout, Govert J van Dam, Paul Lam Corstjens, Angela van Diepen, Maria Yazdanbakhsh, Cornelis H Hokke, Meta Roestenberg","doi":"10.1172/JCI185422","DOIUrl":"https://doi.org/10.1172/JCI185422","url":null,"abstract":"<p><strong>Background: </strong>Partial protective immunity to schistosomiasis develops over time, following repeated praziquantel treatment. Moreover, animals develop protective immunity after repeated immunisation with irradiated cercariae. Here, we evaluated development of natural immunity through consecutive exposure-treatment cycles with Schistosoma mansoni (Sm) in healthy, Schistosoma-naïve participants using single-sex controlled human Sm infection.</p><p><strong>Methods: </strong>Twenty-four participants were randomised double-blind (1:1) to either the reinfection group, which received three exposures (week 0,9,18) to 20 male cercariae or the infection control group, which received two mock exposures with water (week 0,9) prior to cercariae exposure (week 18). Participants were treated with praziquantel (or placebo) at week 8, 17 and 30. Attack rates after the final exposure (week 19-30) using serum circulating anodic antigen (CAA) positivity were compared between groups. Adverse events were collected for safety.</p><p><strong>Results: </strong>Twenty-three participants completed follow-up. No protective efficacy was seen, given 82% (9/11) attack rate after the final exposure in the reinfection group and 92% (11/12) in the infection control group (protective efficacy 11%; 95% CI -24% to 35%; p =0.5). Related adverse events were higher after the first infection (45%), compared to the second (27%) and third infection (28%). Severe acute schistosomiasis was observed after the first infections only (2/12 in reinfection group and 2/12 in infection control group).</p><p><strong>Conclusion: </strong>Repeated Schistosoma exposure and treatment cycles resulted in apparent clinical tolerance, with fewer symptoms reported with subsequent infections, but did not result in protection against reinfection.</p><p><strong>Trial registration: </strong></p><p><strong>Clinicaltrials: </strong>gov NCT05085470.</p><p><strong>Funding: </strong>ERC Starting grant (no. 101075876).</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813383","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":"A deep intronic mutation causes RAD50 deficiency through an unusual mechanism of distant exon activation.","authors":"Kristine Bousset, Stefano Donega, Najim Ameziane, Tabea Fleischhammer, Dhanya Ramachandran, Miriam Poley-Gil, Detlev Schindler, Ingrid M van de Laar, Franco Pagani, Thilo Dörk","doi":"10.1172/JCI178528","DOIUrl":"https://doi.org/10.1172/JCI178528","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813382","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":"Red Blood Cells Capture and Deliver Bacterial DNA to Drive Host Responses During Polymicrobial Sepsis.","authors":"L K Metthew Lam, Nathan J Klingensmith, Layal Sayegh, Emily Oatman, Joshua S Jose, Christopher V Cosgriff, Kaitlyn A Eckart, John McGinnis, Piyush Ranjan, Matthew Lanza, Nadir Yehya, Nuala J Meyer, Robert P Dickson, Nilam S Mangalmurti","doi":"10.1172/JCI182127","DOIUrl":"10.1172/JCI182127","url":null,"abstract":"<p><p>Red blood cells (RBCs), traditionally recognized for their role in transporting oxygen, play a pivotal role in the body's immune response by expressing TLR9 and scavenging excess host cell-free DNA. DNA capture by RBCs leads to accelerated RBC clearance and triggers inflammation. Whether RBCs can also acquire microbial DNA during infections is unknown. Murine RBCs acquire microbial DNA in vitro and bacterial-DNA-induced macrophage activation was augmented by WT but not Tlr9-deleted RBCs. In a mouse model of polymicrobial sepsis, RBC-bound bacterial DNA was elevated in WT but not in erythroid Tlr9-deleted mice. Plasma cytokine analysis in these mice revealed distinct sepsis clusters characterized by persistent hypothermia and hyperinflammation in the most severely affected subjects. RBC-Tlr9 deletion attenuated plasma and tissue IL-6 production in the most severe group. Parallel findings in human subjects confirmed that RBCs from septic patients harbored more bacterial DNA compared to healthy individuals. Further analysis through 16S sequencing of RBC-bound DNA illustrated distinct microbial communities, with RBC-bound DNA composition correlating with plasma IL-6 in patients with sepsis. Collectively, these findings unveil RBCs as overlooked reservoirs and couriers of microbial DNA, capable of influencing host inflammatory responses in sepsis.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812296","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":"Estimation of prevalence of autoimmune diseases in the United States using electronic health record data.","authors":"Aaron H Abend, Ingrid He, Neil Bahroos, Stratos Christianakis, Ashley B Crew, Leanna M Wise, Gloria P Lipori, Xing He, Shawn N Murphy, Christopher D Herrick, Jagannadha Avasarala, Mark G Weiner, Jacob S Zelko, Erica Matute-Arcos, Mark Abajian, Philip Ro Payne, Albert M Lai, Heath A Davis, Asher A Hoberg, Chris E Ortman, Amit D Gode, Bradley W Taylor, Kristen I Osinski, Damian N Di Florio, Noel R Rose, Frederick W Miller, George C Tsokos, DeLisa Fairweather","doi":"10.1172/JCI178722","DOIUrl":"https://doi.org/10.1172/JCI178722","url":null,"abstract":"<p><strong>Background: </strong>Previous epidemiologic studies of autoimmune diseases in the United States (US) have included a limited number of diseases or used meta-analyses that rely on different data collection methods and analyses for each disease.</p><p><strong>Methods: </strong>To estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from six large medical systems in the US. We developed a software program using common methodology to compute the estimated prevalence of autoimmune diseases alone and in aggregate that can be readily used by other investigators to replicate or modify the analysis over time.</p><p><strong>Results: </strong>Our findings indicate that over 15 million people, or 4.6% of the US population, have been diagnosed with at least one autoimmune disease from January 1, 2011, to June 1, 2022, and 34% of those are diagnosed with more than one autoimmune disease. As expected, females (63% of those with autoimmune disease) were almost twice as likely as males to be diagnosed with an autoimmune disease. We identified the top 20 autoimmune diseases based on prevalence and according to sex and age.</p><p><strong>Conclusion: </strong>Thus, we provide, for the first time, a large-scale prevalence estimate of autoimmune disease in the US by sex and age.</p><p><strong>Funding: </strong>Autoimmune Registry Inc., the National Heart Lung and Blood Institute, the National Center for Advancing Translational Sciences, the Intramural Research Program of the National Institute of Environmental Health Sciences.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813384","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":"Fusobacterium nucleatum promotes colorectal cancer through neogenesis of tumor stem cells.","authors":"Qinying Wang, Tingting Hu, Qinyuan Zhang, Yichi Zhang, Xiaoxu Dong, Yutao Jin, Jinming Li, Yangyang Guo, Fanying Guo, Ziying Chen, Peijie Zhong, Yongzhi Yang, Yanlei Ma","doi":"10.1172/JCI181595","DOIUrl":"https://doi.org/10.1172/JCI181595","url":null,"abstract":"<p><p>Intestinal stem cells are crucial for maintaining intestinal homeostasis, yet their transformation into tumor stem cells in the context of microbial infection remains poorly understood. Fusobacterium nucleatum (F. nucleatum) is frequently associated with the onset and progression of colorectal cancer (CRC). In this study, we uncovered that F. nucleatum colonized the depths of gut crypts in both human CRC patients and mouse models. Through single-cell sequencing analysis, we demonstrated that F. nucleatum infection reprogrammed crypt cells and activated LY6A+ revival stem cells (RSCs), promoting their hyperproliferation and subsequent transformation into tumor stem cells, which accelerated intestinal carcinogenesis. Mechanistically, we identified LY6A as a GPI-anchored membrane receptor for F. nucleatum. Upon binding, F. nucleatum induced upregulation of RPS14 via the LY6A receptor, driving RSC hyperactivity and tumorigenic conversion. Functional studies showed that genetic ablation of Ly6a in intestinal epithelial cells or Rps14 in LY6A+ RSCs substantially reduced F. nucleatum colonization and tumorigenesis. Moreover, clinical CRC cohorts analysis revealed a strong correlation between F. nucleatum infection, RSC expansion, and elevated RPS14 expression in tumor tissues. These findings highlight an alternative F. nucleatum-LY6A-RPS14 signaling axis as a critical driver of CRC progression and propose potential therapeutic targets for effective CRC intervention.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801034","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":"MicroRNAs: Where brilliance, perseverance, and ambition converged.","authors":"Rares Drula, George A Calin","doi":"10.1172/JCI189625","DOIUrl":"https://doi.org/10.1172/JCI189625","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801036","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}