دورية أكاديمية
أعرض في EDS

A Genome-Wide Knockout Screen in Human Macrophages Identified Host Factors Modulating Salmonella Infection.

التفاصيل البيبلوغرافية
العنوان: A Genome-Wide Knockout Screen in Human Macrophages Identified Host Factors Modulating Salmonella Infection.
المؤلفون: Yeung ATY; Wellcome Sanger Institute, Hinxton, United Kingdom., Choi YH; Wellcome Sanger Institute, Hinxton, United Kingdom.; DGIST, Department of New Biology, Daegu, Republic of Korea., Lee AHY; Centre for Microbial Diseases and Immunity Research, Vancouver, Canada., Hale C; Wellcome Sanger Institute, Hinxton, United Kingdom., Ponstingl H; Wellcome Sanger Institute, Hinxton, United Kingdom., Pickard D; Wellcome Sanger Institute, Hinxton, United Kingdom.; University of Cambridge Department of Medicine, Cambridge, United Kingdom., Goulding D; Wellcome Sanger Institute, Hinxton, United Kingdom., Thomas M; Wellcome Sanger Institute, Hinxton, United Kingdom., Gill E; Centre for Microbial Diseases and Immunity Research, Vancouver, Canada., Kim JK; DGIST, Department of New Biology, Daegu, Republic of Korea., Bradley A; Wellcome Sanger Institute, Hinxton, United Kingdom.; University of Cambridge Department of Medicine, Cambridge, United Kingdom., Hancock REW; Wellcome Sanger Institute, Hinxton, United Kingdom.; Centre for Microbial Diseases and Immunity Research, Vancouver, Canada., Dougan G; Wellcome Sanger Institute, Hinxton, United Kingdom gd312@medschl.cam.ac.uk.; University of Cambridge Department of Medicine, Cambridge, United Kingdom.
المصدر: MBio [mBio] 2019 Oct 08; Vol. 10 (5). Date of Electronic Publication: 2019 Oct 08.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101519231 Publication Model: Electronic Cited Medium: Internet ISSN: 2150-7511 (Electronic) NLM ISO Abbreviation: mBio Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Society for Microbiology
مواضيع طبية MeSH: Disease Resistance* , Gene Knockout Techniques* , Genetic Testing*, Host-Derived Cellular Factors/*immunology , Macrophages/*immunology , Salmonella/*immunology, Endocytosis ; Host-Derived Cellular Factors/genetics ; Humans ; Macrophages/microbiology ; Models, Theoretical ; Salmonella/growth & development ; Salmonella Infections/immunology ; THP-1 Cells
مستخلص: A genome-scale CRISPR knockout library screen of THP-1 human macrophages was performed to identify loss-of-function mutations conferring resistance to Salmonella uptake. The screen identified 183 candidate genes, from which 14 representative genes involved in actin dynamics ( ACTR3 , ARPC4 , CAPZB , TOR3A , CYFIP2 , CTTN , and NHLRC2 ), glycosaminoglycan metabolism ( B3GNT1 ), receptor signaling ( PDGFB and CD27 ), lipid raft formation ( CLTCL1 ), calcium transport ( ATP2A2 and ITPR3 ), and cholesterol metabolism ( HMGCR ) were analyzed further. For some of these pathways, known chemical inhibitors could replicate the Salmonella resistance phenotype, indicating their potential as targets for host-directed therapy. The screen indicated a role for the relatively uncharacterized gene NHLRC2 in both Salmonella invasion and macrophage differentiation. Upon differentiation, NHLRC2 mutant macrophages were hyperinflammatory and did not exhibit characteristics typical of macrophages, including atypical morphology and inability to interact and phagocytose bacteria/particles. Immunoprecipitation confirmed an interaction of NHLRC2 with FRYL, EIF2AK2, and KLHL13. IMPORTANCE Salmonella exploits macrophages to gain access to the lymphatic system and bloodstream to lead to local and potentially systemic infections. With an increasing number of antibiotic-resistant isolates identified in humans, Salmonella infections have become major threats to public health. Therefore, there is an urgent need to identify alternative approaches to anti-infective therapy, including host-directed therapies. In this study, we used a simple genome-wide screen to identify 183 candidate host factors in macrophages that can confer resistance to Salmonella infection. These factors may be potential therapeutic targets against Salmonella infections.
(Copyright © 2019 Yeung et al.)
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معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust; Canada CIHR
فهرسة مساهمة: Keywords: CRISPR; Salmonella; bacteria; genome-wide screen; macrophages
المشرفين على المادة: 0 (Host-Derived Cellular Factors)
تواريخ الأحداث: Date Created: 20191010 Date Completed: 20200430 Latest Revision: 20210110
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC6786873
DOI: 10.1128/mBio.02169-19
PMID: 31594818
قاعدة البيانات: MEDLINE
الوصف
تدمد:2150-7511
DOI:10.1128/mBio.02169-19