JCI insight最新文献_第7页

Activation of lung megakaryocyte α7 nAChR exacerbates allergic airway inflammation via IL-33/p38 MAPK signaling. 肺巨核细胞α7 nAChR的激活通过IL-33/p38 MAPK信号通路加重了过敏性气道炎症。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.202201

Hang Wu, Rujia Tao, Shitao Xie, Yao Zhou, Jin-Fu Xu, Zhenwei Xia, Xiao Su

{"title":"Activation of lung megakaryocyte α7 nAChR exacerbates allergic airway inflammation via IL-33/p38 MAPK signaling.","authors":"Hang Wu, Rujia Tao, Shitao Xie, Yao Zhou, Jin-Fu Xu, Zhenwei Xia, Xiao Su","doi":"10.1172/jci.insight.202201","DOIUrl":"10.1172/jci.insight.202201","url":null,"abstract":"The cholinergic antiinflammatory pathway attenuates lung inflammation via the α7 nicotinic acetylcholine receptor (α7 nAChR) on immune cells. However, the role of α7 nAChR on lung megakaryocytes (Mks) in allergic airway inflammation remains unknown. In this study, allergen-challenged mouse models were used with conditional Mk-specific Chrna7 knockout, pharmacological activation (GTS-21), and Mk reconstitution. IL-33 expression and p38 MAPK signaling were assessed. We found that allergen challenge upregulated α7 nAChR specifically in lung Mks. Mk-specific Chrna7 deletion significantly alleviated allergic airway inflammation, whereas GTS-21 exacerbated inflammation via an Mk-dependent mechanism. Reconstitution with α7 nAChR+ Mks restored airway inflammatory responses. Mechanistically, α7 nAChR activation promoted Mk IL-33 synthesis and secretion through p38 MAPK signaling. Taken together, our results show that α7 nAChR on lung Mks plays a proinflammatory role in allergic airway inflammation, challenging its classical antiinflammatory paradigm and revealing pathogenic mechanisms.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 17","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906248","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}

引用次数: 0

Spatial multiomics in biomedical research: advances beyond transcriptomics. 生物医学研究中的空间多组学：转录组学之外的进展。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.206951

Xinchen Mao, Zhuo Chen, Emily J Hwang, Jun Liu, Junrou Huang, Haikuo Li

引用次数: 0

Type 3 Inflammation-Specific Keratinocyte Glutaminolysis Promotes Skin Inflammation. 3型炎症特异性角化细胞谷氨酰胺溶解促进皮肤炎症。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.203626

Yongfei Hu, Hai Yu, Kaiyu Liang, Liyan Yuan, Wenjun Zhang, Zhe Zhuang, Suyun Ji, Xichun Xia

{"title":"Type 3 Inflammation-Specific Keratinocyte Glutaminolysis Promotes Skin Inflammation.","authors":"Yongfei Hu, Hai Yu, Kaiyu Liang, Liyan Yuan, Wenjun Zhang, Zhe Zhuang, Suyun Ji, Xichun Xia","doi":"10.1172/jci.insight.203626","DOIUrl":"https://doi.org/10.1172/jci.insight.203626","url":null,"abstract":"Inflammatory cytokines reprogram keratinocyte metabolism, but the metabolic pathways that couple immune signals to pathological epidermal growth remain incompletely defined. Here, we identify GLS1-mediated glutaminolysis as a metabolic program preferentially induced in keratinocytes under type 3 inflammatory conditions. Integrated transcriptomic, metabolomic, genetic, and functional analyses showed that IL-17A induced GLS1 expression and glutaminolysis in keratinocytes. Keratinocyte-specific Gls1 deletion reduced the intracellular availability of arginine, proline, and methionine, impaired amino acid-dependent mTORC1 activation, disrupted redox homeostasis, and limited keratinocyte proliferation. Amino acid or antioxidant supplementation partially rescued these defects, whereas rapamycin blocked the amino acid-mediated proliferative rescue. Gls1 deletion did not impair steady-state skin development or homeostasis and did not alter MC903-induced type 2 dermatitis, but it delayed wound re-epithelialization and attenuated IMQ-induced psoriasiform inflammation. Loss of keratinocyte GLS1 also reduced epidermal chemokine expression and the accumulation of neutrophils and IL-17A-producing γδ T cells, revealing a role for glutaminolysis in amplifying epithelial-immune crosstalk. These findings define GLS1-mediated glutaminolysis as a context-specific metabolic checkpoint linking type 3 inflammation to keratinocyte proliferation and cutaneous immune amplification, and support locally or temporally controlled GLS1 inhibition as a potential therapeutic strategy for psoriasis.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912011","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}

引用次数: 0

Fracture healing requires proliferation of callus cells at early and mature stages of osteoblast differentiation. 骨折愈合需要骨痂细胞在成骨细胞分化的早期和成熟阶段的增殖。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 eCollection Date: 2026-10-08 DOI: 10.1172/jci.insight.196751

Nicole R Gould, Andre F Coello, Jennifer A McKenzie, Mariam Obaji, Tiandao Li, Katherine R Hixon, Leyi Chen, Kristen Barwick, Tiffany Lee, Bo Zhang, David Ornitz, Matthew J Silva

{"title":"Fracture healing requires proliferation of callus cells at early and mature stages of osteoblast differentiation.","authors":"Nicole R Gould, Andre F Coello, Jennifer A McKenzie, Mariam Obaji, Tiandao Li, Katherine R Hixon, Leyi Chen, Kristen Barwick, Tiffany Lee, Bo Zhang, David Ornitz, Matthew J Silva","doi":"10.1172/jci.insight.196751","DOIUrl":"10.1172/jci.insight.196751","url":null,"abstract":"Fractures heal by rapid formation of mineralized callus, a process requiring periosteal cell proliferation and differentiation. Our objective was to dissect the contribution of proliferating osteoblast-lineage cells to fracture callus formation. First, mice expressing thymidine kinase (TK) in 3.6Col1a1-lineage cells were treated with ganciclovir (GCV) to ablate proliferating osteolineage cells for 5 or 10 days. Immunostaining demonstrated that this approach specifically depleted TK+ proliferating cells in the bony regions of the callus, while sparing other proliferating cells. Single-cell RNA-seq of callus cells revealed that GCV-treated Col1-TK mice had fewer osteoblasts and chondrocytes than controls, with more myofibroblasts and immune cells, consistent with fibrous nonunion. In controls, 15%-30% of callus cells expressing the early osteoblast marker Osterix (Osx, Sp7) and the late marker osteocalcin (Ocn, Bglap) were in the cell cycle. Next, we targeted proliferating osteolineage cells at different stages of differentiation by crossing Osx-CreERT2, Ocn-Cre, and Dmp1-CreERT2 mice with ROSA-TK mice. Following fracture, each Cre ROSA-TK mouse line exhibited decreased callus bone volume and a shift from callus bone to fibrous tissue. Therefore, during fracture repair, proliferation of callus cells at early and mature stages of osteoblast differentiation is critical to the formation of a mineralized callus that is essential for healing.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912088","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}

引用次数: 0

EPHA2 and WNT reciprocally regulate MAPK-dependent gene expression in a pancreatic cancer model. 在胰腺癌模型中，EPHA2和WNT相互调节mapk依赖基因的表达。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 eCollection Date: 2026-10-08 DOI: 10.1172/jci.insight.202630

Shawn R Wadia, Changyuan Hu, Siddhi Patnaik, Shreya Sridharan, Roger J Daly, David M Virshup, Babita Madan

{"title":"EPHA2 and WNT reciprocally regulate MAPK-dependent gene expression in a pancreatic cancer model.","authors":"Shawn R Wadia, Changyuan Hu, Siddhi Patnaik, Shreya Sridharan, Roger J Daly, David M Virshup, Babita Madan","doi":"10.1172/jci.insight.202630","DOIUrl":"10.1172/jci.insight.202630","url":null,"abstract":"Wnt signaling drives tumorigenesis in multiple cancers, in part through complex interactions with other oncogenic pathways including the MAPK cascade. In Wnt-addicted cancers, pharmacological and genetic inhibition of Wnt signaling activates multiple RTKs, increases ERK phosphorylation, and induces MAPK target gene expression, but the specific RTKs responsible for this MAPK hyperactivation are not known. Here, we performed phosphotyrosine-targeted mass spectrometry, which revealed robust phosphorylation of EPHA2 and EGFR upon Wnt inhibition. Unexpectedly, we found that in xenografts, EPHA2 suppresses EGFR and ERK activation. Most notably, the increased ERK phosphorylation observed in EPHA2-KO tumors is transcriptionally inert, as there is no concomitant increase in MAPK target gene expression until concomitant Wnt inhibition. This suggests a Wnt-activated transcriptional repressor such as GATA3 that gates MAPK signaling in Wnt-high cancers. Although Wnt-high KRAS-mutant cancers are resistant to erlotinib alone, adding a Wnt inhibitor mitigates this resistance. Additionally, loss of EPHA2 enhances these cancers' sensitivity to both erlotinib and Wnt inhibitors. Our studies therefore identify therapeutic vulnerabilities in Wnt-high tumors, even within traditionally EGFR inhibitor-resistant, RAS-mutant contexts.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912100","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}

引用次数: 0

Human Y chromosome pan-organ mapping reveals progressive mosaic loss from normal to cancer. 人类Y染色体泛器官图谱揭示了从正常到癌症的渐进镶嵌损失。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.201996

Arkadiusz Gertych, Huihui Ye, Xingyu Chen, Eric Vail, V Krishnan Ramanujan, Lauren Brady, Lawrence D True, Peter S Nelson, Peter R Carroll, Dan Theodorescu

{"title":"Human Y chromosome pan-organ mapping reveals progressive mosaic loss from normal to cancer.","authors":"Arkadiusz Gertych, Huihui Ye, Xingyu Chen, Eric Vail, V Krishnan Ramanujan, Lauren Brady, Lawrence D True, Peter S Nelson, Peter R Carroll, Dan Theodorescu","doi":"10.1172/jci.insight.201996","DOIUrl":"10.1172/jci.insight.201996","url":null,"abstract":"Background: Loss of the Y chromosome (LOY) is a frequent event in male tumors and has been linked to cancer progression. However, the degree of mosaic LOY (mLOY) within normal tissues from men with or without cancer remains uncharacterized.Methods: Here we used a FISH-based assay targeting X- and Y-chromosome centromeres to perform a pan-organ analysis of mLOY in 1,000 male tissue samples from 405 individuals representing 11 organs. Automated image processing generated a quantitative FISH-based mLOY score (YchrFISH) that we validated against a transcriptomic surrogate of Y-chromosome dosage from RNA-seq data.Results: mLOY burden varied by tumor type, with highest degree in colorectal carcinoma. Across tissue groups, YchrFISH scores declined progressively from normal tissues of cancer-free men to histologically normal tissues adjacent to cancer and carcinoma (P < 0.0001). Paired analyses confirmed consistently greater mLOY in malignant compared with tumor-adjacent histologically normal tissue in different organs. Spatially resolved RNA-seq maps of bladders removed for cancer demonstrated a transcriptional gradient of Y-chromosome loss from normal urothelium through intraepithelial neoplasia to invasive carcinoma.Conclusion: mLOY gradients exist across histologically normal and malignant tissues, consistent with the concept of field cancerization. Our findings support epithelial mLOY as a biomarker of early malignant transformation and, to our knowledge, a previously unrecognized hallmark of male oncogenesis.Funding: NIH grants R35CA294022, P01CA163227, and P50CA97186 (the Pacific Northwest Prostate Cancer SPORE) and the Institute for Prostate Cancer Research.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 17","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906220","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}

引用次数: 0

Estrogen promotes tumor phenotypes in ER+ and ER- breast cancer through UGDH-GPR30. 雌激素通过UGDH-GPR30促进ER+和ER-乳腺癌的肿瘤表型。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.197357

Meghan J Price, Annee D Nguyen, Corinne H Strawser, Trupti Trivedi, Cesar Cd Baeta, Catherine Lavau, Jovita K Byemerwa, Debarati Mukherjee, Suzanne E Wardell, Sandeep Artham, Vardhman Kumar, Shyni Varghese, C Rory Goodwin

{"title":"Estrogen promotes tumor phenotypes in ER+ and ER- breast cancer through UGDH-GPR30.","authors":"Meghan J Price, Annee D Nguyen, Corinne H Strawser, Trupti Trivedi, Cesar Cd Baeta, Catherine Lavau, Jovita K Byemerwa, Debarati Mukherjee, Suzanne E Wardell, Sandeep Artham, Vardhman Kumar, Shyni Varghese, C Rory Goodwin","doi":"10.1172/jci.insight.197357","DOIUrl":"10.1172/jci.insight.197357","url":null,"abstract":"Estrogen can promote aggressive tumor phenotypes in estrogen receptor-positive (ER+) breast cancer; however, ER- cell lines are not widely considered estrogen responsive. Noncanonical estrogen-stimulated pathways such as the membrane-bound G protein-coupled estrogen receptor (GPR30) can mediate migratory and proliferative phenotypes in breast cancer and are postulated to promote resistance to aromatase therapies. Moreover, dysregulation of UDP-glucose 6-dehydrogenase (UGDH), a ubiquitously expressed enzyme critical to the metabolism of UDP-glucuronic acid into extracellular matrix precursors and hormone regulation, is associated with tumorigenesis. Here, we illustrated the impact of estrogen stimulation on tumor phenotypes in ER+ and ER- cell models in vitro and in vivo. We then demonstrated UGDH's association with metastatic breast cancer via single-cell sequencing of patient specimens. Genetic knockdown of UGDH blunted estrogen-stimulated tumor phenotypes in vitro, ex vivo, and in vivo using both ER+ and ER- breast cancer lines. Finally, we demonstrated that UGDH knockdown blunted noncanonical estrogen stimulation through GPR30. Ultimately, our study validated prior studies demonstrating estrogen-responsive malignant phenotypes in ER- breast cancer and demonstrated that estrogen-stimulated breast cancer progression can be mediated through noncanonical pathways (e.g., UGDH/GPR30), regardless of ER status.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 17","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906227","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}

引用次数: 0

Allotopic expression of ND6 restores vision in a mitochondrial disease model. 异位表达ND6在线粒体疾病模型中恢复视力

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 eCollection Date: 2026-10-08 DOI: 10.1172/jci.insight.209108

Cheng Ai, Huiying Li, Jing Wu, Tianwei Zhou, Jing Wang, Shao-Hui Pan, Jun Yu, Douglas C Wallace, Min-Xin Guan

{"title":"Allotopic expression of ND6 restores vision in a mitochondrial disease model.","authors":"Cheng Ai, Huiying Li, Jing Wu, Tianwei Zhou, Jing Wang, Shao-Hui Pan, Jun Yu, Douglas C Wallace, Min-Xin Guan","doi":"10.1172/jci.insight.209108","DOIUrl":"10.1172/jci.insight.209108","url":null,"abstract":"Mutations in mitochondrial DNA (mtDNA) cause various mitochondrial diseases that are currently incurable. Allotopic expression of nucleus-recoded mitochondrial genes represents a promising therapeutic strategy, given its demonstrated capacity to restore mitochondrial function in human cell models harboring mtDNA mutations. However, the in vivo evaluation of allotopic gene therapy has been hindered by optimization challenges and the lack of appropriate animal models. Here, we overcome these limitations by utilizing an optimized AAV2-ND6 construct with codon optimization and mitochondrial targeting sequence in a mouse model bearing the homoplasmic ND6P25L mutation, which recapitulates Leber hereditary optic neuropathy (LHON). High-dose administration of the AAV2-ND6 construct resulted in robust, sustained expression within the retina and optic nerve without apparent systemic toxicity. Strikingly, we compared the therapeutic efficacy in mutant mice at different ages and presymptomatic intervention with AAV2-ND6 effectively attenuated disease progression, mitigated retinal cellular deficiencies and optic nerve damage, and restored visual function in ND6P25L mice. Mechanistically, allotopic ND6 expression markedly rescued the mitochondrial dysfunction, corrected dysregulated retinol metabolism and phototransduction pathways, and suppressed apoptotic processes in the mutant retina. Our study validates the safety and therapeutic potential of allotopic expression in vivo and provides critical mechanistic insights into its role in treating LHON and other mitochondrial diseases.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912080","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}

引用次数: 0

Urinary YKL-40 as a diagnostic biomarker for cystinosis. 尿YKL-40作为胱氨酸病的诊断生物标志物。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.206193

Jason H Greenberg, Serena D Souza, Heather R Thiessen Philbrook, Wassim Obeid, Avi Z Rosenberg, Elena Levtchenko, Koenraad Veys, Susan L Furth, Chirag R Parikh

{"title":"Urinary YKL-40 as a diagnostic biomarker for cystinosis.","authors":"Jason H Greenberg, Serena D Souza, Heather R Thiessen Philbrook, Wassim Obeid, Avi Z Rosenberg, Elena Levtchenko, Koenraad Veys, Susan L Furth, Chirag R Parikh","doi":"10.1172/jci.insight.206193","DOIUrl":"10.1172/jci.insight.206193","url":null,"abstract":"Early diagnosis of cystinosis is critical to limit disease progression. YKL-40, a protein in the chitinase family, released by inflammatory cells, may be a useful biomarker for cystinosis. In a case-control study of 10 children with cystinosis and 20 without cystinosis, matched by age and baseline eGFR, we measured urine YKL-40, NGAL, and EGF. A lateral flow device (LFD) for YKL-40 was also developed and tested. Urine YKL-40 was over 200-fold higher in children with cystinosis (64.6 ng/mL [IQR: 23.4, 83.8]) compared with controls (0.3 [IQR: 0.3, 0.79]; P = 0.0001) with excellent diagnostic discrimination (AUC = 0.99) that was superior to other biomarkers. LFD measurements for YKL-40 showed similar results (AUC = 0.93). YKL-40 results were verified in 5 cystinosis patients, and YKL-40 staining was markedly higher in kidney biopsies from cystinosis patients than in healthy controls. Urine YKL-40 has excellent diagnostic potential for cystinosis, and point-of-care technologies may facilitate early screening and management of this disease.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 17","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905728","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}

引用次数: 0

Discovery of CD4+ T cell-recognized B. pertussis antigens that reduce airway colonization. 发现CD4+ T细胞识别的百日咳抗原减少气道定植。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.199234

Mohamed M Shamseldin, Jesse M Hall, Griffin M Lawrence, Gabrielle M Hernandez, Yue Liu, Alexa R Aubrey, Eva K Verzani, Rajendar Deora, Amy Lovett-Racke, Jennifer G Abelin, Purnima Dubey

{"title":"Discovery of CD4+ T cell-recognized B. pertussis antigens that reduce airway colonization.","authors":"Mohamed M Shamseldin, Jesse M Hall, Griffin M Lawrence, Gabrielle M Hernandez, Yue Liu, Alexa R Aubrey, Eva K Verzani, Rajendar Deora, Amy Lovett-Racke, Jennifer G Abelin, Purnima Dubey","doi":"10.1172/jci.insight.199234","DOIUrl":"10.1172/jci.insight.199234","url":null,"abstract":"Despite widespread vaccination, Bordetella pertussis (Bp) cases are resurging globally. Although CD4+ T cells are known to be essential for sustained protection, the antigens they recognize are not fully characterized, hindering vaccine refinement. Using immunopeptidomics, bioinformatics, and functional T cell assays, we identified high-affinity epitopes from reference and clinical Bp strains presented on MHC-II I-Ab. A subset of these epitopes stimulated systemic and mucosal CD4+ T cells of mice immunized with heat-killed Bp, and peripheral blood T cells from humans vaccinated with the whole-cell pertussis vaccine. Mice immunized with a subunit vaccine comprising two recombinant proteins identified in our screen were subsequently challenged with Bp. Bacterial burden was nearly eliminated from the lower respiratory tract and significantly reduced in the upper respiratory tract. Th1/Th17-polarized CD4+ tissue-resident memory T cells (Trms) were induced in nasal and pulmonary tissues. Depleting memory CD4+ T cells before challenge abolished protection, confirming that antigen-specific CD4+ T cells are critical for clearing Bp from the respiratory tract. Our integrated antigen identification and T cell assay approach revealed previously untested Bp antigens that elicit protective CD4+ T cell-mediated immunity, suggesting that incorporating them into new vaccines may help curb the resurgence of pertussis.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 17","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906281","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}

引用次数: 0