Global efforts to eradicate malaria are crucially dependent on scientists' ability to outsmart the malaria parasite. And Plasmodium falciparum is notoriously clever: It is quick to develop resistance against medications and has such a complex life cycle that blocking it effectively with a vaccine has thus far proved elusive.
In a new study reported in Nature Communications, researchers have shown that Plasmodium falciparum is even more devious than previously thought: Not only does it hide from the body's immune defenses, it employs an active strategy to deceive the immune system.
In the new study, the team discovered that in parallel with communicating with other parasites, Plasmodium falciparum uses this same communication channel for yet another purpose: to deliver a misleading message to the infected person's immune system. Within the first 12 hours after infecting red blood cells, the parasites send out DNA-filled nanovesicles that penetrate cells called monocytes.
Normally, monocytes form the immune system's first line of defense against foreign invasion, sensing danger from afar and alerting other immune mechanisms to mount an effective response. Naturally, the immune system dispatches its next line of defense to these cells.
But in fact, the nanovesicles have converted the monocytes into decoys. While the immune system is busy defending the organism against fake danger, the real infection proceeds inside red blood cells, allowing the parasite to multiply unhindered at dizzying speed. By the time the immune system discovers its mistake, precious time has been lost, and the infection is much more difficult to contain.
The team has identified a key molecular sensor, a protein called STING that becomes activated when the parasite's nanovesicles penetrate monocytes. STING subsequently activates the kinase TBK1, which phosphorylates the transcription factor IRF3, causing IRF3 to translocate to the nucleus and induce STING-dependent gene expression.It is STING that delivers the fake alert to the immune system, tricking it into "thinking" that its monocytes are in danger. When the scientists "knocked out" the gene that manufactures STING, the chain of molecular reactions generating the misleading alert was interrupted.
"We've discovered a subversive strategy the malaria parasite employs in order to thrive in human blood," senior author says. "By interfering with this subversion of the immune system, it may be possible in the future to develop ways of blocking malarial infection."