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April 25, 2017

CRISPR and Stem Cells Identify Novel Chlamydia Drug Targets

  • Researchers at the Wellcome Trust Sanger Institute and their colleagues at the University of British Columbia have developed a novel method for studying how the bacterium Chlamydia trachomatis interacts with the human immune system. They used a combination of gene-editing and stem cell technologies to make the model that helped lead to the discovery of two genes from our immune system, interferon regulatory factor 5 (IRF5) and interleukin-10 receptor subunit alpha (IL-10RA), as key players in fighting a Chlamydia infection. 

    The results, reported in Nature Communications ("Exploiting Induced Pluripotent Stem Cell-Derived Macrophages to Unravel Host factor Influencing Chlamydia trachomatis Pathogenesis"), identify novel drug targets for the sexually transmitted disease.

    In this study, scientists created macrophages from human induced pluripotent stem cells to study Chlamydia infection. Macrophages have a crucial role in killing Chlamydia to limit the infection. The macrophages produced responded to the disease in a similar way to those taken from human blood, meaning they are more human-like than those produced by previous methods.

    This new model will enable scientists to study how Chlamydia interacts with the human immune system to avoid antibiotics and spread, according to Amy Yeung, Ph.D., first author from the Wellcome Trust Sanger Institute.

    "Chlamydia is tricky to study because it can permeate and hide in macrophages where it is difficult to reach with antibiotics. Inside the macrophage, one or two Chlamydia cells can replicate into hundreds in just a day or two, before bursting out to spread the infection," she said. "This new system will allow us to understand how Chlamydia can survive and replicate in human macrophages and could have major implications for the development of new drugs."

    The new model has advantages over previous methods that used macrophages either derived from mice, which differ from humans in their immune response, or immortalized human macrophage cell lines, which are genetically different from normal macrophages, she added.

    In the study, scientists used CRISPR/Cas9 to genetically edit the human induced pluripotent stem cells, and then see the effects of the genetic manipulation on the resulting macrophages' ability to fight infection. 

    Robert Hancock, Ph.D., lead author from the University of British Columbia and associate faculty member at the Wellcome Trust Sanger Institute, noted that, "We can knock out specific genes in stem cells and look at how the gene editing influences the resulting macrophages and their interaction with Chlamydia. We're effectively sieving through the genome to find key players and can now easily see genes that weren't previously thought to be involved in fighting the infection."

    The team discovered two macrophage genes in particular that were key to limiting Chlamydia infection—IRF5 and IL-10RA. When these genes were switched off, the macrophages were more susceptible to Chlamydia infection. The results suggest these genes could be drug targets for new chlamydia treatments.

    "This system can be extended to study other pathogens and advance our understanding of the interactions between human hosts and infections," explained Gordon Dougan, Ph.D., senior author from the Wellcome Trust Sanger Institute. "We are starting to unravel the role our genetics play in battling infections, such as Chlamydia, and these results could go toward designing more effective treatments in the future."

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