Integrating GWAS with bulk and single-cell RNA-sequencing reveals a role for LY86 in the anti-Candida host response


Autoři: Dylan H. de Vries aff001;  Vasiliki Matzaraki aff001;  Olivier B. Bakker aff001;  Harm Brugge aff001;  Harm-Jan Westra aff001;  Mihai G. Netea aff002;  Lude Franke aff001;  Vinod Kumar aff001;  Monique G. P. van der Wijst aff001
Působiště autorů: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands aff001;  Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands aff002;  Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania aff003
Vyšlo v časopise: Integrating GWAS with bulk and single-cell RNA-sequencing reveals a role for LY86 in the anti-Candida host response. PLoS Pathog 16(4): e32767. doi:10.1371/journal.ppat.1008408
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008408

Souhrn

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.

Klíčová slova:

Candida – Candida albicans – Gene expression – Genome-wide association studies – Immune response – Monocytes – Quantitative trait loci – Small interfering RNAs


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