WEHI team gets behind malaria's cloak of invisibility

In the science fiction series Star Trek, the Klingons use cloaking technology to render their spaceships invisible to the Enterprise's sophisticated sensor systems. But like many other futuristic ideas, that cloaking technology was invented by nature first. The tiny vampire Plasmodium falciparum, which causes the deadliest form of human malaria, has up to 60 ways of cloaking itself against its host's immune defences.

In a research paper published this week in the international journal Cell, research teams at Melbourne's Walter and Eliza Hall Medical Research Institute (WEHI), led by Prof Alan Cowman and Dr Brendan Crabb, explain how P. falciparum performs its 'now you see me, now you don't' act.

It has been known for some time that the parasite can switch antigenic guise when it comes under fire from the immune system, by switching on different variants of its VAR gene family.

Cowman said P. falciparum cells have 60 different VAR genes, scattered in clusters on all of its chromosomes.

The total number of VAR variants in the parasite's global gene pool probably runs to tens of thousands, but each individual cell has a choice of only 60, of which just one is active at any time. The other 59 are inactivated by acetylation, swaddled in heterochromatin and parked in a quiet corner of the cell nucleus.

Using RNAi gene-knockout technology, Cowman and Crabb have shown that the rest are silenced by a gene called SIR2 (silence information regular).

Repressing SIR2 itself causes all the VAR genes to switch on simultaneously, cloaking the parasite the antigenic equivalent of Joseph's coat of many colours.

Cowman said a drug that suppressed SIR2 would force the parasite to reveal its full wardrobe of to the immune system, which could then deploy antibodies and cytotoxic T-cells to destroy any antigenic variant, and retain a 'memory' of each for future, rapid responses.

Alternatively, a drug that locked SIR2 'on', preventing the parasite switching to new antigenic guise when its current cloak reaches its use-by date, would give the immune system a fixed target.

Cowman said the discovery may explain the repeated waves of parasitaemia seen in patients with untreated falciparum malaria.

The immune system eventually learns to target the cloak worn by the early wave of parasites -- typically numbering around a trillion cells -- and eliminates them, leaving a residue of some 1 to 2 per cent of parasites that have randomly switched to a new VAR antigen.

These survivors then undergo clonal expansion to create a new population, establishing a boom-and-bust cycle that manifests as repeated waves or parasitaemia. Cowman said earlier research support the idea that each wave of parasitaemia involves new antigens.

"Now that we have revealed the parasite's mysterious mechanism of disguise and survival, scientists can look forward to designing molecules or drug candidates that will upset the successful masquerade," Cowman said.

Other members of the discovery team were Manoj Duraisingh, Till Voss, Alison Marty, Jennifer Thompson, Robert Good and Michael Duffy (University of Melbourne).

The research was funded by the National Health and Medical Research Council of Australia, the Wellcome Trust and the Howard Hughes Medical Research Institute (HHMI) -- both Cowman and Crabb are HHMI international research scholars.