دورية أكاديمية
Multiple receptor tyrosine kinases regulate dengue infection of hepatocytes.
| العنوان: | Multiple receptor tyrosine kinases regulate dengue infection of hepatocytes. |
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| المؤلفون: | Bourgeois NM; Department of Global Health, University of Washington, Seattle, WA, United States.; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, United States., Wei L; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, United States., Ho NNT; Department of Global Health, University of Washington, Seattle, WA, United States.; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, United States., Neal ML; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, United States., Seferos D; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, United States., Tongogara T; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, United States., Mast FD; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, United States., Aitchison JD; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, United States.; Department of Pediatrics, University of Washington, Seattle, WA, United States., Kaushansky A; Department of Global Health, University of Washington, Seattle, WA, United States.; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, United States.; Department of Pediatrics, University of Washington, Seattle, WA, United States. |
| المصدر: | Frontiers in cellular and infection microbiology [Front Cell Infect Microbiol] 2024 Mar 22; Vol. 14, pp. 1264525. Date of Electronic Publication: 2024 Mar 22 (Print Publication: 2024). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Frontiers Media SA Country of Publication: Switzerland NLM ID: 101585359 Publication Model: eCollection Cited Medium: Internet ISSN: 2235-2988 (Electronic) Linking ISSN: 22352988 NLM ISO Abbreviation: Front Cell Infect Microbiol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Lausanne : Frontiers Media SA |
| مواضيع طبية MeSH: | Dengue* , Dengue Virus*/physiology, Humans ; Receptor, EphA1 ; Hepatocytes/metabolism ; Tyrosine ; Virus Replication |
| مستخلص: | Introduction: Dengue is an arboviral disease causing severe illness in over 500,000 people each year. Currently, there is no way to constrain dengue in the clinic. Host kinase regulators of dengue virus (DENV) infection have the potential to be disrupted by existing therapeutics to prevent infection and/or disease progression. Methods: To evaluate kinase regulation of DENV infection, we performed kinase regression (KiR), a machine learning approach that predicts kinase regulators of infection using existing drug-target information and a small drug screen. We infected hepatocytes with DENV in vitro in the presence of a panel of 38 kinase inhibitors then quantified the effect of each inhibitor on infection rate. We employed elastic net regularization on these data to obtain predictions of which of 291 kinases are regulating DENV infection. Results: Thirty-six kinases were predicted to have a functional role. Intriguingly, seven of the predicted kinases - EPH receptor A4 (EPHA4), EPH receptor B3 (EPHB3), EPH receptor B4 (EPHB4), erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 2 (FGFR2), Insulin like growth factor 1 receptor (IGF1R), and ret proto-oncogene (RET) - belong to the receptor tyrosine kinase (RTK) family, which are already therapeutic targets in the clinic. We demonstrate that predicted RTKs are expressed at higher levels in DENV infected cells. Knockdown of EPHB4, ERBB2, FGFR2, or IGF1R reduces DENV infection in hepatocytes. Finally, we observe differential temporal induction of ERBB2 and IGF1R following DENV infection, highlighting their unique roles in regulating DENV. Discussion: Collectively, our findings underscore the significance of multiple RTKs in DENV infection and advocate further exploration of RTK-oriented interventions against dengue. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Bourgeois, Wei, Ho, Neal, Seferos, Tongogara, Mast, Aitchison and Kaushansky.) |
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| فهرسة مساهمة: | Keywords: dengue (DENV); flavivirus; host-pathogen interactions; kinase regression; kinase signaling; neglected tropical disease |
| المشرفين على المادة: | EC 2.7.10.1 (Receptor, EphA1) 42HK56048U (Tyrosine) |
| تواريخ الأحداث: | Date Created: 20240408 Date Completed: 20240409 Latest Revision: 20240409 |
| رمز التحديث: | 20240409 |
| مُعرف محوري في PubMed: | PMC10995305 |
| DOI: | 10.3389/fcimb.2024.1264525 |
| PMID: | 38585651 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2235-2988 |
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| DOI: | 10.3389/fcimb.2024.1264525 |