WCSU Professor Studies Apoptosis and Drug Resistance in Malaria

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Three hundred years ago, the term “malaria,” or “bad air,” was coined in Italy as a way to describe a sickness contracted in marshes and other areas with noxious fumes. It wasn’t until 1880 that the organism itself was first noticed in a patient’s blood—a discovery that earned Dr. Alphonse Laveran the Nobel Prize in 1907—and it was proposed that mosquitoes could transmit the parasite. Plasmodium falciparum malaria has grown to become the most ubiquitous parasitic disease in human beings, with nearly 200 million cases reported each year, due to the complexity of its life cycle and its resistance to drug treatment.

Dr. Judith Prieto, an assistant professor of chemistry at Western Connecticut State University (WCSU), was raised and educated in Colombia, where she worked as an undergraduate senior in a malaria research unit. “Just like with any scientific endeavor, you pretty much end up studying the same thing you start with, be it a particular question or problem that might be presented to you,” said Dr. Prieto. “For me, that was to quantify a particular antimalarial drug in the blood of monkeys that were being tested. As I kept reading about [malaria] and the issues involved, I started wanting to understand how is it that we need to keep testing for new drugs? Why are there no drugs that are efficient enough for the malaria parasite? What is it about the parasite that makes it so hard to work with?”

Of course, once you start answering one question, other questions start opening up. One quandary, for instance, was that “higher organisms have a mechanism in which cells kill themselves, or commit suicide for the benefit of the greater organism. For the greater good, so to speak,” said Dr. Prieto. For complex organisms like human beings, programmed cell death, called apoptosis, is an advantageous process in growth and survival. “This is not supposed to happen for single-celled organisms, where the cell is supposed to reproduce no matter what.”

But it appears that the single-celled organisms in the same family as malaria have proteins involved in this same type of suicide programming. “That means that they seem to kill themselves for the benefit of the cells that are surrounding them, all the other ‘partner cells.’ So this cellular suicide is what has been driving my research most of the time, and what we want to understand is does this actually happen? Are the proteins active, and are they actually committing suicide or not? And if there is actually a pathway for this apoptosis to happen, can we use it to our advantage?”

There is plenty of evidence that this pathway, or series of chemical reactions in a cell, takes place when the parasite is in the mosquito, which is referred to as the ‘vector.’ “There is a collection of parasites growing in the gut of the mosquito, and the population has to be controlled, otherwise the mosquito will die and the disease won’t be transmitted,” said Dr. Prieto. “So, it has been proven that the pathway takes place in the vector. Does it take place in the host? That’s the bigger question. That’s what I want to answer—does the parasite also control the population of how many parasites are in the red blood cells or at any given point?”

Malaria has a complex life cycle—particularly for a single-celled organism—which prevents scientists from fighting it quickly enough to get a real edge. When we develop a drug, the parasite develops a resistance to it after around 15 years of consistent usage, and because it reproduces very frequently, it mutates quickly. “We can usually have a drug kill the parasite in one phase, but it’s still living in all the other phases,” says Dr. Prieto. “It survives in the mosquito or it keeps going in the liver cells, even though you may have killed it in the red blood cells. It makes it a much harder fight.”

So, how do you eventually get an edge over a parasite that is consistently reproducing and adapting like malaria? “In the 1980s, the parasite developed a resistance against these two sets of drugs, sulfadoxine and pyrimethamine, and it did so by mutating one of its exposed proteins,” says Dr. Prieto. “The interesting thing is that once you take the drug pressure away, the parasite will eventually turn the mutated protein back to its wild type state. It turns out that whatever those mutations were, which the parasite took on, were not actually convenient to the parasite, and instead were only taken on to fight the drugs. That’s a very interesting avenue to look at.”

A common question is whether scientists can create an all-encompassing vaccine, but the potential effectiveness of a vaccine is similarly vexing. “The issue with the vaccines is that when the parasite presents itself, there’s only one short period of time—when the parasite is injected from the mosquito into the host before it travels to the liver—where our immune system actually ‘sees’ the parasite,” says Dr. Prieto. After that, the parasite will be hidden in our cells, and since our immune system won’t attack our own cells, the parasite is protected. “So, there’s this very short time where the parasite is exposed to the immune system and has proteins exposed to the outside. There are about 60 different variants of this protein, so if our immune system creates immunity against one set of proteins, then the next time you get infected, that parasite will have another of the 60 variants of the protein exposed to the outside.”

The malaria parasite has a significant amount of versatility, which it uses constantly to ‘fool’ our immune system, but Dr. Prieto’s research is addressing what she believes are some of the most viable avenues in addressing the parasite. “I have certain avenues that I like to research, like the avenue of apoptosis, but there are other areas that I like to open up to my students to research. The questions really are never-ending, and it’s really interesting to read the research literature because the amount of progress being made is gigantic.”

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