Exploiting induced pluripotent stem cell-derived macrophages to unravel host factors influencing Chlamydia trachomatis pathogenesis

Amy T. Y. Yeung, Christine Hale, Amy H. Lee, Erin E. Gill, Wendy Bushell, David Parry-Smith, David Goulding, Derek Pickard, Theodoros Roumeliotis, Jyoti Choudhary, Nick Thomson, William C. Skarnes, Gordon Dougan and Robert E. W. Hancock ()
Additional contact information
Amy T. Y. Yeung: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Christine Hale: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Amy H. Lee: Centre for Microbial Diseases and Immunity Research, University of British Columbia
Erin E. Gill: Centre for Microbial Diseases and Immunity Research, University of British Columbia
Wendy Bushell: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
David Parry-Smith: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
David Goulding: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Derek Pickard: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Theodoros Roumeliotis: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Jyoti Choudhary: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Nick Thomson: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
William C. Skarnes: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Gordon Dougan: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Robert E. W. Hancock: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Chlamydia trachomatis remains a leading cause of bacterial sexually transmitted infections and preventable blindness worldwide. There are, however, limited in vitro models to study the role of host genetics in the response of macrophages to this obligate human pathogen. Here, we describe an approach using macrophages derived from human induced pluripotent stem cells (iPSdMs) to study macrophage–Chlamydia interactions in vitro. We show that iPSdMs support the full infectious life cycle of C. trachomatis in a manner that mimics the infection of human blood-derived macrophages. Transcriptomic and proteomic profiling of the macrophage response to chlamydial infection highlighted the role of the type I interferon and interleukin 10-mediated responses. Using CRISPR/Cas9 technology, we generated biallelic knockout mutations in host genes encoding IRF5 and IL-10RA in iPSCs, and confirmed their roles in limiting chlamydial infection in macrophages. This model can potentially be extended to other pathogens and tissue systems to advance our understanding of host-pathogen interactions and the role of human genetics in influencing the outcome of infections.

Date: 2017
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DOI: 10.1038/ncomms15013

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