New drug targets identified to defend against chlamydia infections using CRISPR and stem cells

Human induced pluripotent stem cell derived macrophages (iPSDMs) provide a cell-based model system to study chlamydia infection in the laboratory. Amy Yeung from Wellcome Trust Sanger Institute explains how she used this model in combination with CRISPR-Cas 9 technology to explore the potential of the two genes, IRF5 and IL10RA, as drug targets…

Chlamydia is one of the most common sexually transmitted infections in the UK and globally, accounting for 46.1% of all STIs diagnosed in 2015 (reported by Public Health England). There are various species of the bacteria that can cause infection: the most common being C. trachomatis. Chlamydia is often dubbed the ‘silent disease’, as it rarely produces symptoms in infected individuals early on. However, left untreated, chlamydial infection can trigger pelvic inflammatory disease, leading to infertility or life-threatening ectopic pregnancy. Chlamydial infections can also lead to blindness and reactive arthritis. Although chlamydia is a major bacterial pathogen in the community, it remains one of the less well-studied microorganisms. Antibiotics such as azithromycin and doxycycline are commonly used to treat infections but, due to the increasing threat of antibiotic resistance, there is an urgent need to develop new therapeutics. However, in order to do so we must first understand how chlamydia interacts with our immune system.

Immune cells, such as macrophages, play critical roles in limiting chlamydial infections. The infiltration of macrophages into infected tissues also leads to inflammation. Moreover, the persistence of chlamydia in macrophages can contribute to chronic inflammation and delayed response to antibiotics. Therefore, it is necessary to identify what controls chlamydial survival or killing in human macrophages in order to identify the appropriate therapeutic strategies to eliminate infections.

One of the major hurdles to studying the complex interactions between chlamydia and human macrophages is the lack of an appropriate cell-based model system to study infections in the laboratory. Macrophages derived from mice are commonly used, but there are critical differences in response between mouse and human macrophages. Other common models include the use of immortalised human macrophage lines (cells engineered to proliferate indefinitely), but their genomic arrangements are far removed from the normal genetic state. Primary macrophages derived from human blood have also been used, but the macrophage responses can vary between donors, and primary macrophages are inherently difficult to genetically manipulate.

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