Researchers at Weill Cornell Medicine have discovered how Plasmodium falciparum, the parasite that causes malaria when transmitted through a mosquito bite, can hide from the body’s immune system, sometimes for years. The team’s preclinical study showed that the parasite can shut down a key set of genes, rendering itself “immunologically invisible.”
Their results indicate 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. “This finding provides another piece of the puzzle as to why malaria has been so difficult to eradicate,” said study co-lead Francesca Florini, PhD, a research associate in microbiology and immunology at Weill Cornell Medicine. Malaria infects 300-500 million people yearly, resulting in nearly 600,000 deaths globally.
“Current campaigns to control malaria focus on treating people, usually children, who show symptoms,” added Kirk Deitsch, PhD, professor of microbiology and immunology at Weill Cornell Medicine. “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.”
Deitsch is senior author of the researchers’ published paper in Nature Microbiology, titled “scRNA-seq reveals transcriptional plasticity of var gene expression in Plasmodium falciparum for host immune avoidance.”
![Dirk Deitsch, PhD [WCM]](https://www.genengnews.com/wp-content/uploads/2025/05/Low-Res_deitsch-headshot-e1747424969393-295x300.jpg "Dirk Deitsch, PhD [WCM]")
Dirk Deitsch, PhD [WCM]
Malaria remains a prominent disease in many tropical countries, and Plasmodium falciparum is responsible for most infections and deaths, the authors explained. Once inside the human body, the parasite enters red blood cells (RBCs) 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 var genes, each of which 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 team explained further that the parasites “… export several adhesins to the RBC surface, including P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1), enabling attachment to the vascular endothelium, thereby avoiding splenic clearance.”
The only problem with this strategy is that, within about a week, the immune system can produce antibodies that recognize the adhesive protein. “PfEMP1 is the primary target of the humoral immune response …,” the team continued. 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. “Plasmodium falciparum evades antibody recognition through transcriptional switching between members of the var gene family.”
Deitsch noted, “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.” 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. “.. chronic, asymptomatic infections have been identified lasting for a decade or more, long after the var gene repertoire would have been exhausted, leaving unexplained how such parasites avoid elimination and remain seemingly undetected by the immune system,” the scientists stated.
![Francesca Florini, PhD [WCM]](https://www.genengnews.com/wp-content/uploads/2025/05/Low-Res_francesca_florini-head-shot-300x272.jpg "Francesca Florini, PhD [WCM]")
Francesca Florini, PhD [WCM]
To solve this riddle, 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. “We show that in addition to mono-allelic var gene expression, individual parasites can simultaneously express multiple var genes or enter a state in which little or no var gene expression is detectable,” they stated.
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,” Deitsch explained.
But the stealthy parasites that shut down all their var genes were a surprise. The authors noted, “Reduced var gene expression resulted in greatly decreased antibody recognition of infected cells. This transcriptional flexibility provides parasites with greater adaptive capacity and could explain the antigenically ‘invisible’ parasites observed in chronic asymptomatic infections. Florini also commented, “This ‘null state,’ in which parasites display little or no var gene expression, would have been impossible to identify using population-based assays. 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,” Deitsch said. “If a red cell can sit there for 24 hours, that’s long enough for the parasite to complete its life cycle.”
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.
The post Malaria Turns Down Genes to Evade Immunity, Enable Chronic Infection appeared first on GEN - Genetic Engineering and Biotechnology News.
Their results indicate 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. “This finding provides another piece of the puzzle as to why malaria has been so difficult to eradicate,” said study co-lead Francesca Florini, PhD, a research associate in microbiology and immunology at Weill Cornell Medicine. Malaria infects 300-500 million people yearly, resulting in nearly 600,000 deaths globally.
“Current campaigns to control malaria focus on treating people, usually children, who show symptoms,” added Kirk Deitsch, PhD, professor of microbiology and immunology at Weill Cornell Medicine. “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.”
Deitsch is senior author of the researchers’ published paper in Nature Microbiology, titled “scRNA-seq reveals transcriptional plasticity of var gene expression in Plasmodium falciparum for host immune avoidance.”
Dirk Deitsch, PhD [WCM]
Malaria remains a prominent disease in many tropical countries, and Plasmodium falciparum is responsible for most infections and deaths, the authors explained. Once inside the human body, the parasite enters red blood cells (RBCs) 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 var genes, each of which 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 team explained further that the parasites “… export several adhesins to the RBC surface, including P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1), enabling attachment to the vascular endothelium, thereby avoiding splenic clearance.”
The only problem with this strategy is that, within about a week, the immune system can produce antibodies that recognize the adhesive protein. “PfEMP1 is the primary target of the humoral immune response …,” the team continued. 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. “Plasmodium falciparum evades antibody recognition through transcriptional switching between members of the var gene family.”
Deitsch noted, “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.” 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. “.. chronic, asymptomatic infections have been identified lasting for a decade or more, long after the var gene repertoire would have been exhausted, leaving unexplained how such parasites avoid elimination and remain seemingly undetected by the immune system,” the scientists stated.
Francesca Florini, PhD [WCM]
To solve this riddle, 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. “We show that in addition to mono-allelic var gene expression, individual parasites can simultaneously express multiple var genes or enter a state in which little or no var gene expression is detectable,” they stated.
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,” Deitsch explained.
But the stealthy parasites that shut down all their var genes were a surprise. The authors noted, “Reduced var gene expression resulted in greatly decreased antibody recognition of infected cells. This transcriptional flexibility provides parasites with greater adaptive capacity and could explain the antigenically ‘invisible’ parasites observed in chronic asymptomatic infections. Florini also commented, “This ‘null state,’ in which parasites display little or no var gene expression, would have been impossible to identify using population-based assays. 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,” Deitsch said. “If a red cell can sit there for 24 hours, that’s long enough for the parasite to complete its life cycle.”
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.
The post Malaria Turns Down Genes to Evade Immunity, Enable Chronic Infection appeared first on GEN - Genetic Engineering and Biotechnology News.