September 20, 2023

Weill Cornell Lab Uncovers New Information About Malaria Transmission Pathway

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Researchers at Weill Cornell recently published a study in Nature Microbiology that highlights the newly discovered intricacies of the malaria transmission cycle. The results of their study could have implications for how scientists approach malaria prevention in the future.

Malaria is a life-threatening disease transmitted by mosquitoes that disproportionately affects tropical countries. According to the Center for Disease Control and Prevention, malaria is a leading cause of death and disease in low- and middle-income countries and remains a significant global health problem.

The cause of malaria is a microscopic organism called a protozoan — more specifically the parasitic protozoan, plasmodium. This parasite lives in two different hosts: humans and mosquitoes. While there are five species of plasmodium that routinely cause malaria in humans, the species P. falciparum is most life-threatening, making it a favorable research target for labs like Kafsack’s.

When an infected mosquito bites a person, it transmits a form of the parasite called sporozoites to the human host. The sporozoites then travel through the blood vessels and infect liver cells, where they reproduce asexually. The parasites then burst out of the liver cell in a new form called merozoites and enter the bloodstream, where they target red blood cells. Inside red blood cells, the merozoites form a ring-like structure called a trophozoite. 

Most trophozoites reproduce asexually and release more merozoites into the bloodstream, but some perform sexual reproduction, forming cells called gametocytes. While the asexual blood stages are not infectious to a mosquito, gametocytes are.

Because malaria is not directly transmitted between humans, the parasite must return to a mosquito host to complete its transmission cycle — this is accomplished through a blood meal, in which the mosquito ingests the malaria parasites in their sexual form from the human. 

While asexual replication keeps the human host infected with malaria, sexual replication is crucial for transmission to a mosquito host, and both are needed to complete the malaria cycle. 

The regulation of developmental transitions in these blood cells is the primary focus of the paper’s senior author, Prof. Björn Kafsack, microbiology and immunology. First author Chantal Harris grad performed most of the experiments for the study in Kafsack’s lab, according to Kafsack.

The way that gametocytes regulate their formation involves a transcription factor, AP2-G.

When AP2-G is turned on, allowing for gene expression, parasites become gametocytes in the human host. When ingested by a mosquito, these gametocytes mediate the transmission of malaria to the mosquito host. 

“Basically, the question is how does the parasite control how many gametocytes it makes, or how often does it turn a gene on,” Kafsack said.

When chromatin — the building blocks of chromosomes made of DNA and proteins — are very tightly packed, gametocytes cannot be formed. When chromatin is not packed densely enough, the gene is not silenced properly, resulting in gametocyte formation.

Kafsack’s research stems from a separate 2017 study, which found that lysoPC, a lipid biomolecule, suppresses P. falciparum’s gametocyte formation. Kafsack and his team wanted to find the link between lysoPC and the AP2-G transcription factor.

The lab found that the parasite uses a choline molecule to create its membrane. LysoPC is used to synthesize the precursor for choline. However, when the precursor is scarce, the parasite finds a new way to synthesize choline, consuming a molecule called S-adenosylmethionine, or SAM, in the process. The consumption of SAM impairs the dense packing of chromatin that is needed to silence AP2-G, which results in gametocyte formation. 

“If the parasite has to make a lot of phosphocholine itself, the brake pads wear down on the silencing of AP2-G, so silencing becomes leaky, so you make more gametocytes,” Kafsack said. 

This conclusion provides insight into how gametocyte formation is regulated in malaria parasites. 

The application of Kafsack’s research is largely disease prevention. Though altering gametocyte formation would not benefit an already infected individual, it could prevent the future spread of the disease. Because P. falciparum is so adaptable to human and mosquito hosts, malaria has proven to be a very difficult disease to treat — however, Kafsack’s research sheds light on important molecular mechanisms that regulate infection.

“To stop transmission, we need to not only treat people who are sick but also find people who are asymptomatic, because asymptomatic carriers carry gametocytes,” Kafsack said. “We need drugs that kill the asexual stages, which is what gives people malaria, but we also need to find ways of blocking transmission, and understanding how that works is what my lab does.”

Anna Labiner can be reached at [email protected].