Malaria parasites survive their stay in a malaria mosquito thanks to an enzyme that chemically modifies one of their surface proteins. An international team led by Leiden parasitologist Chris Janse just presented this discovery in the journal PNAS.

It concerns parasites (Plasmodium sp.) in the sporozoite stage. Sporozoites develop in the intestines of an infected mosquito and then migrate via the body fluids to the salivary glands as the last stop before transferring to humans or animals. Contrary to expectations, the mosquito’s natural defence system leaves them alone during the journey. The parasite produces a glutaminyl cyclase enzyme, QC for short, which can convert the amino acid building blocks glutamine and glutamic acid into (cyclic) pyroglutamic acid.

QC is only successful if such a building block is at the N-terminal end of a protein. This is, for example, the case for the circumsporozoite protein (CSP), which is abundantly present on the surface of all Plasmodium sporozoites.

After a simple genetic modification, which strips CSP of the only glutamine building block accessible to QC, the sporozoites suddenly appear to be noticed by the mosquito’s immune system. This in turn triggers the production of the colouring agent melanin, with which the parasites are encapsulated – a typical insect method of neutralising intruders. An alternative modification, which makes QC production impossible, has the same effect. How this fundamental knowledge can be used against malaria is not yet immediately obvious, but it is useful to know.

For the time being, it is unclear how glutamine triggers the immune system. But the mechanism does not seem unique. In 2019, a group of Dutch researchers led by Ton Schumacher and Ferenc Scheeren revealed that something similar plays around the membrane protein CD47, which protects human cells from their own immune system. Block a glutaminyl cyclase, in this case abbreviated as QPCTL, and CD47 no longer does. It ended, of course, with the fervent wish to be able to selectively suppress QPCTL in tumour cells – whether that will work remains to be seen.