Researchers at Weill Cornell Medicine have discovered how a parasite that causes malaria when transmitted through a mosquito bite can hide from the body's immune system, sometimes for years. It turns out that the parasite, Plasmodium falciparum, can shut down a key set of genes, rendering itself "immunologically invisible."
"This finding provides another piece of the puzzle as to why malaria has been so difficult to eradicate," said Dr. Francesca Florini , research associate in microbiology and immunology at Weill Cornell Medicine who co-led the study. Malaria infects 300-500 million people yearly, resulting in nearly 600,000 deaths globally.
The preclinical results, published May 16 in Nature Microbiology, reveal that in regions where malaria is endemic, asymptomatic adults likely harbor undetectable parasites which mosquitos may pick up and transfer to the next person they bite.
"Current campaigns to control malaria focus on treating people, usually children, who show symptoms," said Dr. Kirk Deitsch , professor of microbiology and immunology at Weill Cornell Medicine, the paper's senior author. "These findings suggest that we need to consider asymptomatic adults who can carry potentially transmissible parasites—which means eliminating malaria from any geographical region is going to be more complicated than anticipated."
Avoiding Elimination
Once inside the human body, the parasite enters red blood cells to replicate—but it must avoid alerting the immune system or being removed by the spleen, which filters out defective blood cells. Its solution to escaping these potential perils hinges on a suite of about 60 genes called var; each var gene encodes a protein that can insert itself onto the surface of red blood cells.
When the parasite switches on one of these var genes, the protruding protein causes the red cell to adhere to the blood vessel wall, allowing the cell—and its resident parasites—to avoid a trip to the spleen. The only problem with this strategy is that, within about a week, the immune system can produce antibodies that recognize the adhesive protein. To get around this immune counterattack, the parasite shuts off that var gene and expresses a different one from its collection, thereby avoiding detection and prolonging the infection.
"The paradigm has been that the parasite has a strict, mutually exclusive expression mechanism, meaning that it always expresses one—and only one—var gene at a time," Dr. Deitsch said. But what happens after the parasite runs through the whole set? Reactivating one they used previously would trigger rapid immune elimination. Yet, a chronic malaria infection can persist for a decade or more.
To solve this riddle, Dr. Florini and graduate student Joseph Visone used single-cell sequencing technologies to assess how individual parasites manage var gene expression. They discovered that while many do activate only a single var gene at a time, some switch on two or three, while others don't express any at all.
Shutting Down, Hiding Out
The parasites expressing a couple of var genes were likely caught in the act of switching between one and another. "There's a transient stage when both genes are on, and we happen to be capturing the moment of the switch," Dr. Deitsch explained.
But the stealthy parasites that shut down all their var genes were a surprise. "This 'null state,' in which parasites display little or no var gene expression, would have been impossible to identify using population-based assays," Dr. Florini said. "It highlights a new aspect of how malaria escapes recognition by our immune system."
However, without var gene expression the parasites also lose the ability to cling to blood vessel walls, so how are they avoiding the spleen's filtration system? "We suspect that they hide in the bone marrow or in an expandable pocket of non-circulating red cells that pools in the center of the spleen," Dr. Deitsch said. "If a red cell can sit there for 24 hours, that's long enough for the parasite to complete its life cycle."
Dr. Deitsch plans to conduct fieldwork in West Africa to locate these hidden anatomical reservoirs. Finding them—and learning how malaria parasites exploit this newly discovered mechanism for escaping elimination—could provide novel strategies for addressing the problem of chronic malaria infections.
This work was supported by the National Institutes of Health (AI 52390, AI 99327 and an F31 Predoctoral Fellowship F31AI164897), the Swiss NSF (Early Postdoc. Mobility grant P2BEP3_191777) and the William Randolph Hearst Foundation.
