Novel drug targets identified to fight off Chlamydia infections

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A collaborative group of researchers from the Wellcome Trust Sanger Institute (Cambridge, UK) and the University of British Columbia (Vancouver, Canada) have developed a new technique to investigate how Chlamydia trachomatis interacts with the human immune system.

The results, recently published in Nature Communications, highlight IRF5 and IL-10RA as two key genes responsible for fighting off Chlamydia trachomatis infection, offering two new potential targets for future antiviral drug design.

As one of the most commonly sexually transmitted infections in the UK, Chlamydia trachomatis infects more than 200,000 people, each year in England alone. Infection rarely presents with immediate symptoms but can lead to pelvic inflammatory disease and even infertility if left untreated.

With the increasing risk of antibiotic resistance there is a need for novel therapeutics to treat bacterial infections such as Chlamydia trachomatis. For this reason Amy Yeung (Wellcome Trust Sanger Institute) and colleagues set to create a macrophage model, utilizing human induced pluripotent stem cells, to study Chlamydia trachomatis interactions with the immune system.

Yeung noted: “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. 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 team utilized CRISPR/Cas9 technology to genetically edit the human induced pluripotent stem cells to identify genes involved in fighting off Chlamydia infection. Robert Hancock (University of British Columbia) explained: “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.”

Their results revealed two genes which were pivotal in limiting chlamydia infection; IRF5 and IL-10RA. When these genes were down regulated, the macrophages were more susceptible to Chlamydia infection.

Senior author Gordon Dougan (Wellcome Trust Sanger Institute) concluded: “This system can be extended to study other pathogens and advance our understanding of the interactions between human hosts and infections. We are starting to unravel the role our genetics play in battling infections, such as chlamydia, and these results could go towards designing more effective treatments in the future.”

Source: Yeung ATY, Hale C, Lee AH, et al. Exploiting induced pluripotent stem cell-derived macrophages to unravel host factors influencing Chlamydia trachomatis pathogenesis. Nat. Commun. 8, 15013 doi:10.1038/ncomms15013 (2017); www.eurekalert.org/pub_releases/2017-04/wtsi-ncd042417.php

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