While much of the world is rightfully focused on emerging viral infections like coronavirus and ebola, parasitic infections, like malaria, remain some of the world’s most deadly infections. A better understanding of the cellular and molecular makeup for these eukaryotic organisms could help researchers develop better therapies to combat disease. Now, investigators at the University of Nottingham and the University of California, Riverside, have made a major breakthrough in understanding how the parasite that causes malaria is able to multiply at such an alarming rate—a vital clue in discovering how it has evolved, and how it can be stopped.

Finding from the new study—published recently in Cell Reports through an article titled “Plasmodium Condensin Core Subunits SMC2/SMC4 Mediate Atypical Mitosis and Are Essential for Parasite Proliferation and Transmission”—shows how certain molecules play an essential role in the rapid reproduction of parasite cells, which cause this deadly disease. The researchers are hopeful that this could be the next step towards being able to prevent the malaria parasite from reproducing.

“We have tried to understand how these molecules work in the unusual pattern of multiplication by the parasite,” explained senior study investigator Rita Tewari, PhD, professor of parasite cell biology in the School of Life Sciences at the University of Nottingham. “We found that these molecules are there at all the stages of multiplication and they are present only at a certain part of the chromosome, which is called the centromere. We wanted to understand how does the parasite multiply. How do these molecules organize themselves and the DNA in those cells? It is fascinating how a single cell can carry out so many different modes of multiplication, and we need to understand how it does this.”

Malaria is one of the world’s biggest killer infections and is responsible for almost half a million deaths a year, mainly in tropical developing countries. The disease is caused by a single-celled eukaryotic parasite from the genus Plasmodium and is spread from person to person as female Anopheles mosquitoes pick up the parasite from infected people when they bite to get the blood needed to nurture their eggs. Inside the mosquito, the parasites reproduce, multiply, and develop.

“This particular parasite is very adaptable. Even if you kill it in the human bloodstream, it can move into the mosquito stage,” Tewari noted. “Over time, it has adapted to survive and has a lot of genetic plasticity, which is why it is difficult to control the disease.”

As part of their latest research, the team wanted to better understand how the parasite’s cell divides and multiplies especially within a mosquito.

Proteins are large, complex molecules that play many critical roles in the body. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs. Each organism has DNA organized into a certain number of chromosomes and needs condensins in order to “split” this DNA when they multiply. Condensins are large protein complexes that play a central role in chromosome assembly and segregation during mitosis and meiosis.

For Plasmodium, the role of condensins in multiplication and proliferation was unclear. The team looked at two of the crucial condensin subunits, called SMC2 and SMC4, which are required to maintain the structure of chromosomes in a cell of other organisms.

“We examined the role of SMC2 and SMC4, the core subunits of condensin, during endomitosis in schizogony and endoreduplication in male gametogenesis,” the authors wrote. “During early schizogony, SMC2/SMC4 localizes to a distinct focus, identified as the centromeres by NDC80 fluorescence and chromatin immunoprecipitation sequencing (ChIP-seq) analyses, but do not form condensin I or II complexes. In mature schizonts and during male gametogenesis, there is a diffuse SMC2/SMC4 distribution on chromosomes and in the nucleus, and both condensin I and condensin II complexes form at these stages.”

“We need to understand what gives the parasite this plasticity and what it needs at every stage to survive, so it is crucial to understand how the parasite cell divides,” remarked Tewari. “The aim of our research is not to develop a drug immediately but to answer the fundamental question of how the parasite divides and survives and the machinery it uses. The parasite has diverse modes of multiplying, so even if a drug or an effective vaccine is created, they may be able to adapt, and we need to understand how. This is the next step towards that goal.”

After analyzing the parasite, the team found a very unusual type of cell division, showing that the malaria parasite has evolved ways to ensure its survival by way of its cell division.

“By understanding the fundamental aspect of parasite biology, we are decrypting how the parasite divides, and how the different mechanisms regulating cell division can affect the ability of the parasite to thrive and replicate exponentially inside its hosts,” concluded co-senior study investigator Karine Le Roch, PhD, professor at the University of California, Riverside. “If we identify the molecular components that are essential for the replication of this parasite, we will be able to develop novel and long-lasting therapeutic strategies against this devastating disease.”

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