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Lena Pernas sees parasitic infection as a kind of Hunger Games

Mitochondria may lead cell’s attempt to keep nutrients from the invader

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1:47pm, October 4, 2017
Lena Pernas

Toxoplasma is a pretty incredible bug,” says Lena Pernas. But studying the parasite requires gloves, lab coats and goggles. “I wanted hazmat suits.”

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Lena Pernas, 30
Parasitologist
University of Padova

SN 10 - full list of scientistsLena Pernas’ love of parasites began in childhood, when she was plagued with many virtual infections. One of her favorite pastimes as a 9-year-old was playing The Amazon Trail, an educational computer game set near the South American river. One of the dangers players could encounter was malaria, “and I got malaria a lot,” Pernas says. This predicament inspired her to learn about the disease, caused by Plasmodium parasites. Since then, she’s taken every opportunity to study parasites. “It’s been a singular obsession,” she says.

Her parasite of choice eventually became Toxoplasma gondii, which is estimated to infect one-third of humans. Toxoplasma “has an unparalleled mammalian host range,” Pernas says. “It is able to infect basically any warm-blooded animal.” The parasite causes toxoplasmosis, not a terribly bothersome disease for people with a healthy immune system. But the disease can be serious, damaging the eyes and brain, in those with weakened immune systems and in fetuses. (Pregnant women are warned not to handle kitty litter because the parasite can be found in cat feces.)

Pernas, now age 30 and a postdoctoral fellow at the University of Padova in Italy, has upended previous thinking about how this parasite interacts with its host, specifically its interplay with mitochondria. Known as the cell’s energy producers, mitochondria also take part in activities related to immunity and cell death. By studying how mitochondria respond to a parasitic infection, Pernas has begun to probe the ways access to nutrients in the cell — which both the cell and the parasite need — shapes an infection.

Surrounded

A vacuole containing a Toxoplasma parasite is surrounded by mitochondria (indicated by arrows). The parasite and mitochondria fight over fuel, Pernas has found. 

Toxoplasma parasite in a cell vacuole

Studying the vying for nutrients in the cell “will teach us really interesting biology about how the cell senses the presence of a parasite metabolically, and how the cell is able to metabolically respond,” Pernas says — knowledge that could lead to new therapies.

Her discoveries are at the forefront of a new focus in microbiology: viewing the host-pathogen relationship as a “competition for nutrients,” says cell biologist Navdeep Chandel of Northwestern University in Chicago.

When Toxoplasma infects a mammalian cell, it uses part of the cell’s membrane to wrap itself in a little sac, called a vacuole. Early imaging showed a ring of the host cell’s mitochondria surrounding the parasite’s vacuole. But why the mitochondria were there wasn’t clear.

As a graduate student in the lab of microbiologist John Boothroyd of Stanford University School of Medicine, Pernas questioned two existing assumptions: that all three main strains of Toxoplasma interact with mitochondria in the same way, and that the key protein underpinning this relationship had already been found. She was right to ask. In 2014 in PLOS Biology, Pernas, Boothroyd and colleagues reported that when a type I or type III Toxoplasma parasite invades a cell, the mitochondria circle the vacuole. But when the type II parasite enters, the mitochondria don’t gather around.

With this knowledge, Pernas and colleagues identified the correct parasitic protein that tethers the organelles to the vacuole. The three Toxoplasma types have the gene for this protein, called MAF1, but only type I and III make the protein, the researchers found.

Pernas “completely countered the dogma of the field,” Boothroyd says. “Where she excels is having that instinct of saying, ‘This one doesn’t smell right.’”

My dream would be to take the biological research to the global level and figure out how different states of nutrition might affect the human response and the mammalian response to infection.

— Lena Pernas

The discovery of the protein as well as the difference between strains is important, Boothroyd adds. It indicates that the interaction with mitochondria is driven by Toxoplasma, rather than the host cell, and it is likely something the parasite does “to enable survival in some particular subset of hosts,” he says.

Pernas’ postdoctoral work is beginning to uncover how the interaction between the organelles and the parasite affect the invader’s survival. She’s investigating what she calls “the rules that govern the hunger games between the host and parasite.”

To survive, Toxoplasma needs nutrients from its host cell. The parasite is a “prolific scavenger” of fatty acids, Pernas explains. Mitochondria also take up fatty acids, breaking them down for energy. When a type I or III Toxoplasma parasite infects a cell, the mitochondria somehow sense the parasite’s presence and move to surround the vacuole, Pernas says. (Why this doesn’t happen with type II parasites is unclear.)

What comes next is a “fight for fatty acids,” she says.

She has found in unpublished work that the invading parasite starts gobbling up fatty acids. The mitochondria circling the vacuole actually fuse together, allowing them to efficiently use nutrients. This limits the fatty acids that the parasite can get. The parasite sends out the MAF1 protein to tether the mitochondria to the vacuole, which may be what breaks them apart, giving the parasite the greater share of fatty acids.

This fight between host and pathogen for nutrients might be “a widespread phenomenon,” Chandel says.

A better understanding of the battle could lead to new therapies that control an infection by keeping parasites from getting to the cell’s nutrients, Pernas says. She’d also like to study how malnutrition might change the course of an infection. “My dream would be to take the biological research to the global level,” she says, “and figure out how different states of nutrition might affect the human response and the mammalian response to infection.”

Citations

L. Pernas et al. Toxoplasma effector MAF1 mediates recruitment of host mitochondria and impacts the host response. PLOS Biology, April 29, 2014. doi: 10.1371/journal.pbio.1001845.

Further Reading

J. Shugart. Mice lose cat fear for good after infection. Science News. Vol. 184, October 19, 2013.

S. Milius. Little mind benders. Science News, Vol. 183, January 26, 2013, p. 24.

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