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Integrating GWAS with bulk and single-cell RNA-sequencing reveals a role for LY86 in the anti-Candida host response.
PLoS Pathogens ( IF 6.7 ) Pub Date : 2020-04-06 , DOI: 10.1371/journal.ppat.1008408
Dylan H de Vries 1 , Vasiliki Matzaraki 1, 2 , Olivier B Bakker 1 , Harm Brugge 1 , Harm-Jan Westra 1 , Mihai G Netea 2, 3 , Lude Franke 1 , Vinod Kumar 1, 2 , Monique G P van der Wijst 1
Affiliation  

Candida bloodstream infection, i.e. candidemia, is the most frequently encountered life-threatening fungal infection worldwide, with mortality rates up to almost 50%. In the majority of candidemia cases, Candida albicans is responsible. Worryingly, a global increase in the number of patients who are susceptible to infection (e.g. immunocompromised patients), has led to a rise in the incidence of candidemia in the last few decades. Therefore, a better understanding of the anti-Candida host response is essential to overcome this poor prognosis and to lower disease incidence. Here, we integrated genome-wide association studies with bulk and single-cell transcriptomic analyses of immune cells stimulated with Candida albicans to further our understanding of the anti-Candida host response. We show that differential expression analysis upon Candida stimulation in single-cell expression data can reveal the important cell types involved in the host response against Candida. This confirmed the known major role of monocytes, but more interestingly, also uncovered an important role for NK cells. Moreover, combining the power of bulk RNA-seq with the high resolution of single-cell RNA-seq data led to the identification of 27 Candida-response QTLs and revealed the cell types potentially involved herein. Integration of these response QTLs with a GWAS on candidemia susceptibility uncovered a potential new role for LY86 in candidemia susceptibility. Finally, experimental follow-up confirmed that LY86 knockdown results in reduced monocyte migration towards the chemokine MCP-1, thereby implying that this reduced migration may underlie the increased susceptibility to candidemia. Altogether, our integrative systems genetics approach identifies previously unknown mechanisms underlying the immune response to Candida infection.

中文翻译:

将 GWAS 与批量和单细胞 RNA 测序相结合,揭示了 LY86 在抗念珠菌宿主反应中的作用。

念珠菌血流感染,即念珠菌血症,是全世界最常遇到的威胁生命的真菌感染,死亡率高达近 50%。在大多数念珠菌血症病例中,白色念珠菌是罪魁祸首。令人担忧的是,全球易感染患者(例如免疫功能低下的患者)数量的增加导致过去几十年念珠菌血症的发病率上升。因此,更好地了解抗念珠菌宿主反应对于克服这种不良预后和降低疾病发生率至关重要。在这里,我们将全基因组关联研究与白色念珠菌刺激的免疫细胞的批量和单细胞转录组学分析相结合,以进一步了解抗念珠菌宿主反应。我们表明,在单细胞表达数据中对念珠菌刺激的差异表达分析可以揭示宿主对念珠菌的反应所涉及的重要细胞类型。这证实了单核细胞的已知主要作用,但更有趣的是,还揭示了 NK 细胞的重要作用。此外,将批量 RNA-seq 的强大功能与单细胞 RNA-seq 数据的高分辨率相结合,鉴定了 27 个念珠菌反应 QTL,并揭示了本文可能涉及的细胞类型。这些反应 QTL 与关于念珠菌血症易感性的 GWAS 的整合揭示了 LY86 在念珠菌血症易感性中的潜在新作用。最后,实验随访证实 LY86 敲低导致单核细胞向趋化因子 MCP-1 迁移减少,从而暗示这种迁移减少可能是念珠菌病易感性增加的原因。总之,我们的综合系统遗传学方法确定了以前未知的对念珠菌感染的免疫反应的潜在机制。
更新日期:2020-04-06
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