Malaria parasites hijack the immune system by breaking down key genes

Malaria parasites hijack the immune system by breaking down key genes

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 turn off a key set of genes and make 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, a research fellow in microbiology and immunology at Weill Cornell Medicine, who co-led the study. Malaria infects 300-500 million people annually, resulting in nearly 600,000 deaths worldwide.

The preclinical results, published May 16 in Nature Microbiology, show that in regions where malaria is endemic, asymptomatic adults likely have undetectable parasites that mosquitoes can pick up and transmit to the next person they bite.

Current malaria control campaigns focus on treating people, usually children, who exhibit symptoms. These results suggest that we need to consider asymptomatic adults who can potentially carry transmissible parasites – meaning that eliminating malaria from a geographic region will be more complicated than expected. “

Dr. Kirk Deitsch, a professor of microbiology and immunology at Weill Cornell Medicine, the paper's senior author

Avoiding elimination

Once in 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 dangers depends on a suite of about 60 genes called a var. Each Var gene encodes a protein that can attach to the surface of red blood cells.

When the parasite turns on one of these VAR genes, the protruding protein allows the red cell to stick to the blood vessel wall and allows the cell – and its resident parasites – to avoid a trip to the spleen. The only problem with this strategy is that the immune system can produce antibodies that recognize the sticky protein within about a week. To circumvent this immune counterattack, the parasite excludes this var gene and expresses another from its collection, thereby avoiding detection and prolongation of the infection.

“The paradigm was that the parasite has a strict, mutually exclusive expression mechanism, meaning that it always expresses one and only one Var gene at a time,” said Dr. German. But what happens after the parasite runs through the entire set? Reactivation of a previously used one would trigger rapid immunimination. However, a chronic malaria infection can persist for a decade or longer.

To solve this mystery, Dr. Florini and graduate student Joseph Visone used single-cell sequencing technologies to assess how individual parasites manage Var gene expression. They found that while many only turn on a single var gene at a time, some turn on two or three, while others express none at all.

Close, hide

The parasites that expressed a few VAR genes were probably caught in the act of switching between one and another. “There is a transient phase in which both genes are turned on, and we happen to capture the moment of the switch,” explained Dr. German.

But the stealthy parasites shutting down all of their VAR genes were a surprise. “This ‘null state’, in which parasites have little or no VAR gene expression, would have been impossible to identify using population-based assays,” said Dr. Florini. “It highlights a new aspect of how malaria evades detection by our immune system.”

However, without Var gene expression, the parasites also lose the ability to cling to blood vessel walls. So how do they avoid the spleen's filtration system? "We suspect that they hide in the bone marrow or in an expandable pocket of non-circulating red cells clustered in the middle of the spleen," said Dr. German. “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 field research in West Africa to locate these hidden anatomical reservoirs. They find—and learning how malaria parasites exploit this newly discovered escape excretion mechanism—could provide new strategies for treating 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 F31AI164897).

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