Global efforts to eradicate malaria depend on our ability to outsmart the malaria parasite, but 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.
Now, in a new collaborative study reported today in leading journal Nature Communications, scientists have shown that Plasmodium falciparum is even more devious than previously thought.
Not only does it hide from the body’s immune defenses, but it also employs an active strategy to deceive the immune system. If we can develop a way of interrupting this ability, the future would look brighter for blocking one of the world’s deadliest diseases.
The new discoveries harnessed expertise of Weizmann Institute scientists led by Dr Neta Regev-Rudzki in how malaria parasites interact with human cells, with a team from the School of Biochemistry and Immunology in Trinity College Dublin led by Professor Andrew Bowie with experience in understanding how the immune system responds to pathogen DNA.
Among transmittable diseases, malaria is second only to tuberculosis in the number of victims, putting at risk nearly half of the global population. More than 200 million people become infected every year, and about 500,000 die. Most of the casualties are children under five. The disease kills around 1,000 young children every day.
Prior work by Dr Neta Regev-Rudzki unearthed the surprising discovery that malaria parasites communicate with one another while in the incubation stage in the blood by releasing ‘sac-like nanovesicles’.These are less than 1 micron across (about five times smaller than the width of a single strand of spider web silk) and contain small segments of the parasite’s DNA.
Apparently, these signals help the parasites learn when it’s time to start transforming into male and female forms, both of which can be carried by mosquitoes into new hosts. This finding was all the more startling because the nanovesicles need to cross six separate membrane barriers to communicate the message from one parasite inside the red blood cell to another.
In the new study, scientists found that 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; they essentially kick-start the immune response by recruiting other specialist cells to where they are needed.
Professor in Immunology at Trinity College Dublin, Andrew Bowie, said of the new research: “When our immune system responds to pathogens such as malaria, it’s a double-edged sword. The wrong kind of response can actually favour the pathogen and lead to more harm than good. And it seems that malaria parasites actually switch on an immune response to their own DNA to survive longer."
"Here we found the switch mechanism for this, an immune sensor called STING, which senses DNA from the malaria nanovesicles when it is delivered into monocytes. Through STING, malaria parasites fool the immune system into inappropriate responses that favour the parasite’s survival.”
Dr Regev-Rudzki summed up the importance of the study: “We’ve discovered a subversive strategy the malaria parasite employs in order to thrive in human blood. By interfering with this subversion of the immune system, it may be possible in the future to develop ways of blocking malarial infection.”