Toxoplasma gondii, the parasite that causes toxoplasmosis, is thought to infect up to one-third of the global population. Many of those persons have no symptoms, but the parasite can lay latent for years before reactivating to cause disease in anyone who becomes immunocompromised.
Sebastian Lourido, an associate professor of biology at MIT and part of the Whitehead Institute for Biomedical Research, is curious about why this single-celled parasite is so prevalent and what causes it to reappear. In his lab, researchers are figuring out the genetic mechanisms that keep the parasite asleep, as well as the circumstances that cause it to emerge from that state.
Toxoplasma gondii, the parasite that causes toxoplasmosis, is thought to infect up to one-third of the global population. Many of those persons have no symptoms, but the parasite can lay latent for years before reactivating to cause disease in anyone who becomes immunocompromised.
Sebastian Lourido, an associate professor of biology at MIT and part of the Whitehead Institute for Biomedical Research, is curious about why this single-celled parasite is so prevalent and what causes it to reappear. In his lab, researchers are figuring out the genetic mechanisms that keep the parasite asleep, as well as the circumstances that cause it to emerge from that state.
“One of the missions of my lab is to improve our ability to manipulate the parasite genome and to do that at a scale that allows us to ask questions about the functions of many genes, or even the entire genome, in a variety of contexts,” Lourido shares.
There are medications available to treat the acute symptoms of Toxoplasma infection, which include headache, fever, and inflammation of the heart and lungs. However, these medications have little effect on the parasite once it has entered the latent stage. Lourido hopes that his lab’s research may lead to new treatments for this stage, as well as medications to target comparable parasites like Babesia, a tick-borne parasite that is becoming increasingly frequent in New England.
“These parasites impact a large number of individuals, and parasitology frequently receives inadequate attention at the highest levels of scientific study. “It’s critical to bring the latest scientific advances, tools, and concepts to the field of parasitology,” Lourido says.
A passion with microbiology
As a boy in Cali, Colombia, Lourido was fascinated by what he saw through the microscopes in his mother’s medical genetics lab at the University of Valle del Cauca. His father ran the family farm while simultaneously working in government, including acting as interim governor of the state.
“From my mom, I was exposed to the ideas of gene expression and the influence of genetics on biology, and I think that really sparked an early interest in understanding biology at a fundamental level,” according to Lourido. “On the other hand, my dad was in agriculture, and so there were other influences there around how the environment shapes biology.”
Lourido decided to attend college in the United States in part because, in the early 2000s, Colombia was seeing an increase in violence. He was also interested in entering a liberal arts institution, where he could study science and art. He eventually attended Tulane University, where he studied in both fine arts and cell and molecular biology.
Lourido worked primarily in printmaking and painting. He particularly appreciated stone lithography, which entails etching images on enormous slabs of limestone with oil-based inks, processing the images with chemicals, and then transferring the images to paper using a large press.
“I ended up doing a lot of printmaking, which I think attracted me because it felt like a mode of expression that leveraged different techniques and technical elements,” he remarks.
Simultaneously, he worked in a biology lab studying Daphnia, microscopic crustaceans found in fresh water that have helped scientists uncover how animals can generate new features in response to environmental changes. As an undergraduate, he contributed to the development of virus-based methods for introducing novel genes into Daphnia. By the time he graduated from Tulane, Lourido had opted to pursue science instead of painting.
“As an undergraduate, I had developed a strong interest in laboratory science. I appreciated the freedom and creativity that came with it—the ability to work in teams and build on ideas, not having to fully recreate the entire system but instead being able to develop it over time,” he explains.
Lourido worked at the Max Planck Institute for Infection Biology in Germany for two years after graduating college. Lourido worked in Arturo Zychlinksy’s lab, where he studied two bacteria called Shigella and Salmonella, both of which can cause serious infections, including diarrhea. His research there helped to identify how these bacteria enter cells and how they alter the host cells’ own pathways to aid in their replication inside cells.
As a doctoral student at Washington University in St. Louis, Lourido worked in many labs focused on various elements of microbiology, such as virology and bacteriology, but eventually ended up working with David Sibley, a well-known Toxoplasma researcher.
“I had not thought much about Toxoplasma before going to graduate school,” Lourido tells me. “I was very unfamiliar about parasitology in general, despite certain college classes that only touched on the issue briefly. What I appreciated about it was that it was a system about which we knew very little — creatures that differed greatly from textbook models of eukaryotic cells.
Toxoplasma gondii is a member of the apicomplexan parasite family, which includes protozoans that can cause a range of disorders. Toxoplasma gondii can remain hidden from the immune system for decades after infecting a human host, typically in cysts located in the brain or muscles. Lourido was particularly intrigued by the organism because, at the age of 17, he had been diagnosed with toxoplasmosis. His main symptom was swollen glands, but doctors discovered that his blood had antibodies to Toxoplasma.
“It’s fascinating that the parasite survives in all of these people, which account for roughly a quarter to a third of the world’s population.” Chances are I still have living parasites in my body, and if I got immunocompromised, it would be a major issue. “They would begin replicating in an uncontrolled manner,” he explains.
A transforming approach
Toxoplasma’s genetics differ significantly from those of bacteria or other eukaryotes such as yeast and mammals, which makes researching it difficult. Mutating or wiping off parasite genes makes it more difficult to research their activities.
Because of the difficulty, Lourido spent his entire graduate career researching the functions of just a few Toxoplasma genes. After obtaining his PhD, he established his own lab as a fellow at the Whitehead Institute and began working on methods to investigate the Toxoplasma genome on a larger scale, utilizing the CRISPR genome editing tool.
CRISPR allows scientists to systematically knock out every gene in the genome and then investigate how each missing gene impacts parasite function and survival.
“With the application of CRISPR to Toxoplasma, we were able to survey the whole parasite genome. That has been revolutionary,” says Lourido, who joined Whitehead and the MIT faculty in 2017. “Since its original application in 2016, we’ve been able to uncover mechanisms of drug resistance and susceptibility, trace metabolic pathways, and explore many other aspects of parasite biology.”
Using CRISPR-based screens, Lourido’s lab discovered a regulatory gene named BFD1 that appears to promote the expression of genes required for the parasite’s long-term survival within the host. His laboratory has also discovered several of the molecular pathways necessary for the parasite to transition between active and latent stages.
“We’re actively working to understand how environmental inputs end up guiding the parasite in one direction or another,” Lourido explains. “They seem to preferentially go into those chronic stages in certain cells like neurons or muscle cells, and they proliferate more exuberantly in the acute phase when nutrient conditions are appropriate or when there are low levels of immunity in the host.”
