Similarly,
Blocking key hosts can stop:
Researchers from the Francis Crick Institute have mapped the human metabolic paths that CryptosporidiumAn intestinal The parasite requires surviving. Therefore, The closure of these routes can offer a new way of treating patients while avoiding the development of resistance. Moreover, to drugs.
The parasite Cryptosporidium invade. In addition, reproduce inside epithelial cells in the intestine, causing severe diarrhea, which is particularly dangerous for children in endemic regions and people with a weakened immune system. Meanwhile, Despite its major impact on global public health, there is no fully effective treatments.
In a study published today in CellResearchers aimed to understand what this parasite needs the host epithelial cell. Consequently, in order to identify new intervention options.
They conducted a genome scale screening experience. Furthermore, based on CRISPR genetic publishing, which involved systematically deactivating blocking key hosts can stop almost all genes coding for proteins, individually, human intestinal cells. Similarly, The cells were then infected with Cryptosporidium And imagined to see how each gene influenced the survival of parasites.
A metabolic tipping point – Blocking key hosts can stop
The researchers found that the genes involved in the manufacture of cholesterol. Furthermore, an essential component of all human cells, seemed to have opposite effects – a certain stimulating infection and others that block it.
This balance articulated the molecule halfway from the cholesterol production line, called squalène. Eliminate genes before the production of squalène blocked the infection. while eliminating the genes after the production of squalène increased the infection.
Squalène is secreted by the glands of our skin. where it is known to play a protective role, especially against oxidative stress. The team discovered that squalène plays a similar role in the intestine: when squalène levels are high. the reactive species of oxygen (a characteristic blocking key hosts can stop of oxidative stress) are low and vice versa.
The main way that humans control oxidative stress is by a molecule called glutathione. This antioxidant is vital to limit oxidative damage and almost all organisms have the capacity to do so. Surprisingly, the team discovered that, while the Cryptosporidium The parasite uses glutathione, it cannot make its own. This leaves the parasitic dependent on the glutathione of the intestinal cell and particularly vulnerable to oxidative stress.
CryptosporidiumAchille heel
Finally, the team tested if Cryptosporidium‘s Outbuildings on the metabolism of the host could be targeted with drugs.
Squalène production can be directly inhibited with lapquaistat. a drug originally developed for the treatment of high cholesterol, then abandoned later. Lapaquistat directly inhibits the synthesis of squalène. while statins, front -line drugs to lower cholesterol act indirectly and only partially decrease the squalène levels.
In a mouse disease model. Lapaquistat has reduced infection and blocking key hosts can stop completely blocked intestinal damage, suggesting that the drug could be reused to fight Cryptosporidium.
Cryptosporidium Infections can be fatal, especially in children, so we need new treatments.
There are already in -depth security data for lapquaistat, which facilitates the clinical trial to accelerate to Cryptosporidium. And because the drug targets a host route. and not a single parasitic protein, there should be a much greater barrier to resistance to development parasite. “”
Adam Sateuriale, group leader of the Cryptosporidia laboratory
Bishara Marzook, postdoctoral purse at the cryptosporidiosis laboratory and first author, said: “At one point in its evolution, Cryptosporidium has lost the ability to produce glutathione and rather diverts production by the host from this essential molecule. It could be an intelligent way for Cryptosporidium To save your energy for other processes. but we have shown that it could also be its fall.
“We blocking key hosts can stop now have a huge set of data on how almost all genes in human epithelial cells affect Cryptosporidium Infections. Beyond the synthesis of cholesterol. we are now starting to examine other host properties that affect the parasite, opening new doors to research. “”
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