New chlamydia drug targets discovered using CRISPR and stem cells

Drugs for Chlamydia treatment

Adapted Media Release
Scientists
at the Wellcome Trust Sanger Institute and their collaborators at the
University of British Columbia have created an innovative technique for
studying how chlamydia interacts with the human immune system.
Researchers
used a combination of gene editing and stem cell technologies to make the
model. The team identified two genes from our immune system, IRF5 and IL-10RA
as key players in fighting a chlamydia infection. The results, reported in
Nature Communications, identify novel drug targets for the sexually transmitted
disease.
Chlamydia
trachomatis is one of the most common sexually transmitted infections (STIs) in
the UK, with more than 200,000 cases each year in England alone. It is
estimated that 131 million people globally are infected with chlamydia each
year. Often called the ‘silent disease’, as it rarely produces symptoms early
on, chlamydia causes genital infections which can lead to pelvic inflammatory
disease and infertility if left untreated.
The
increasing threat of antibiotic resistance led the World Health Organisation to
issue new guidelines in 2016 for the treatment of chlamydia*. To develop new
therapeutics for the infection, its interaction with our immune system must
first be understood.
In
this study, scientists have created white blood cells, called 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.
Dr
Amy Yeung, first author from the Wellcome Trust Sanger Institute, said:
“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
new model has advantages over previous methods that used macrophages either
derived from mice, which differ from humans in their immune response, or
immortalised human macrophage cell lines, which are genetically different to
normal macrophages.
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.
Dr
Robert Hancock, lead author from the University of British Columbia and
Associate Faculty member at the Wellcome Trust Sanger Institute, said: “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.
Professor
Gordon Dougan, senior author from the Wellcome Trust Sanger Institute said:
“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.”
Article:
Exploiting induced pluripotent stem cell-derived macrophages to unravel host
factors influencing Chlamydia trachomatis pathogenesis, Amy Yeung et al.,
Nature Communications, doi: 10.1038/NCOMMS15013, published online 25 April
2017.
SOURCE: MEDICAL NEWS TODAY
Kayode Ojo
Kayode Emmanuel Ojo is the Co-Founder and Managing Director at SHEFFA Limited. He is presently studying Computer Science at the National Open University, Victoria Island, Lagos.