If you turned on the TV or radio today, you could be easily convinced that COVID-19 was the only disease currently affecting the world. Unfortunately, though, many parts of the globe are battling infectious diseases they have been plagued with for centuries, in addition to the burden from novel coronavirus. Malaria, for instance, has been a scourge on humans, since we began to walk upright (and most likely before). This persistent parasitic infection has left indelible marks on human evolution and our genetic makeup. Our limited understanding of the molecular mechanisms that underscore this disease has only come in recent years, as advanced techniques have allowed us to strip away some of its more elusive characteristics.

Yet, for all the progress that has been made in understanding the malaria parasite, there was one big piece of the puzzle that had been missing until now. When Plasmodium falciparum (the most virulent malaria parasite strain) enters a red blood cell, it resides inside a vacuolar space that it creates during the invasion process. While we know that parasite biomolecules make their way across the membrane, known as the parasitophorous vacuole until recently, it was unclear exactly how the molecules traversed these spaces.

Diagram of the two membrane channels between the malaria parasite vacuole and the red blood cell. [NIH]

“The malaria parasite interfaces with its host erythrocyte (RBC) using a unique organelle, the parasitophorous vacuole (PV),” the authors wrote. “The mechanism(s) are obscure by which its limiting membrane, the parasitophorous vacuolar membrane (PVM), collaborates with the parasite plasma membrane (PPM) to support the transport of proteins, lipids, nutrients, and metabolites between the cytoplasm of the parasite and the cytoplasm of the RBC.”

Now, a team of investigators led by researchers at the National Institutes of Health (NIH) has discovered a set of pore-like holes, or channels, traversing the membrane-bound sac that encloses the deadliest malaria parasite as it infects red blood cells. The channels enable the transport of lipids between the blood cell and parasite, Plasmodium falciparum. The parasite draws lipids from the cell to sustain its growth and may also secrete other types of lipids to hijack cell functions to meet its needs.

Findings from the new study were published recently in Nature Communications through an article titled, “Contacting domains segregate a lipid transporter from a solute transporter in the malarial host-parasite interface.” This new data follows an earlier discovery of another set of channels through the membrane enabling the two-way flow of proteins and non-fatty nutrients between the parasite and red blood cells. Together, the discoveries raise the possibility of treatments that block the flow of nutrients to starve the parasite.

In the current study, the researchers determined that the channels through the vacuole that encloses the parasite are made of Niemann-Pick C1-related protein (PfNCR1). The PfNCR1 channels are restricted to locations where the vacuole membrane touches the parasite’s membrane. The channels the team discovered in the previous study are formed by exported protein 2 (EXP2). Areas of the vacuole membrane containing EXP2 are located far from the parasite’s membrane, at an average distance of 20–40 nm. The researchers believe that the parasite may use this variation in distance to separate the two transport systems.

“We demonstrated that the PV has structure characterized by micrometer-sized regions of especially close apposition between the PVM and the PPM,” the authors noted. “To determine if these contact sites are involved in any sort of transport, we localize the PVM nutrient-permeable and protein export channel EXP2, as well as the PPM lipid transporter PfNCR1. We find that EXP2 is excluded from, but PfNCR1 is included within these regions of close apposition.”

The research team concluded that “the host-parasite interface is structured to segregate those transporters of hydrophilic and hydrophobic substrates.”

With 228 million cases of malaria worldwide in 2018, leading to more than 400,000 deaths, 67% of which were among children under the age of five, according to the World Health Organization, this discovery could open the door to novel treatment options that are most desperately needed.

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