Toxoplasma gondii, the single-celled parasite responsible for toxoplasmosis, is estimated to infect nearly one-third of the global population. While many infected individuals show no symptoms, the organism can remain dormant for years, potentially reactivating to cause disease, especially in those with weakened immune systems.
What makes this parasite so prevalent, and what triggers its reactivation, are central questions for Sebastian Lourido, an associate professor of biology at MIT and a member of the Whitehead Institute for Biomedical Research. In his laboratory, research is delving into the genetic mechanisms that maintain the parasite’s dormant state and the factors that prompt it to reactivate.
“One of my lab’s goals is to enhance our ability to manipulate the parasite’s genome. This will allow us to explore the functions of numerous genes or even the entire genome across various scenarios,” Lourido explains.
While there are treatments available for the acute symptoms of Toxoplasma infection, which can include headache, fever, and inflammation of the heart and lungs, these medications are ineffective during the dormant phase. Lourido aims to develop new therapies that can target this stage, as well as drugs to fight other parasites like Babesia, a tick-borne pathogen on the rise in New England.
“A significant number of individuals are impacted by these parasites, yet parasitology often receives less attention in high-level research discussions. It’s crucial to integrate the latest scientific advancements and tools into the field of parasitology,” states Lourido.
A Passion for Microbiology
Lourido’s fascination with biology began in his childhood in Cali, Colombia, where he marveled at the microscopic wonders he observed in his mother’s medical genetics lab at the University of Valle del Cauca. His father, who ran the family farm and held a government position, also influenced his understanding of the environment’s impact on biology.
“My mother’s work instilled in me an appreciation for gene expression and genetics, while my father’s agricultural background highlighted the interplay between environment and biology,” Lourido reflects. “When it was time for college in the United States, I was drawn to a liberal arts education, wanting to explore both science and art. I chose to attend Tulane University, where I pursued a double major in fine arts and cell and molecular biology.”
As an aspiring artist, Lourido excelled at printmaking and painting, particularly enjoying stone lithography, a process that combines chemical treatments with artistic expression.
“Printmaking fascinated me because it utilizes a variety of techniques and allows for creative expression,” he notes. At the same time, he contributed to biology research on Daphnia, tiny freshwater crustaceans integral to studies on trait development in changing environments. His undergraduate work involved developing methods to use viruses for introducing new genes into these organisms, leading him to choose a career in science over art upon graduation.
“I discovered a deep affection for laboratory research. The creativity and collaborative spirit of science intrigued me, as it allowed for the evolution of ideas over time rather than a complete reinvention,” Lourido shares.
Following his graduation, Lourido spent two years in Germany at the Max Planck Institute for Infection Biology, researching Shigella and Salmonella, bacteria responsible for severe gastrointestinal illnesses. His work aided in uncovering how these pathogens infiltrate cells and manipulate host cellular pathways crucial for their replication.
At Washington University in St. Louis for graduate studies, Lourido explored multiple aspects of microbiology before focusing on Toxoplasma under the guidance of David Sibley, a well-known expert in the field.
“I hadn’t considered Toxoplasma much before graduate school, as my exposure to parasitology had been limited. However, I found it fascinating to study organisms that differ dramatically from typical eukaryotic cell models,” Lourido recalls. His personal connection to the parasite deepened when he was diagnosed with toxoplasmosis at 17, enduring mild symptoms while possessing antibodies against it.
A Groundbreaking Approach
Studying Toxoplasma poses challenges due to its unique genetic makeup, which is distinct from both bacteria and other eukaryotes. This complexity complicates the process of mutating or knocking out genes for functional studies.
Throughout his graduate career, Lourido concentrated on understanding just a few Toxoplasma genes, but upon completing his PhD, he established his lab and began employing CRISPR genome-editing techniques to study the parasite’s genetics on a broader scale.
With CRISPR, scientists can systematically disable genes throughout the genome, allowing for a comprehensive analysis of each gene’s role in parasite viability.
“By adapting CRISPR for Toxoplasma, we’ve transformed our approach to surveying the entire parasite genome. Since we implemented it in 2016, we’ve uncovered mechanisms of drug resistance, traced metabolic pathways, and explored various facets of parasite biology,” says Lourido, who became a member of the Whitehead Institute and joined MIT’s faculty in 2017.
His laboratory has identified a regulatory gene named BFD1, which appears vital for the parasite’s long-term survival within a host. Furthermore, his team has elucidated many of the molecular steps involved when the parasite transitions between active and dormant states.
“We are currently investigating how environmental factors influence the parasite’s directional shift. It seems to favor chronic stages in certain cells, like neurons and muscle cells, while proliferating more actively during the acute phase when nutrient conditions are ideal or the host’s immunity is low,” Lourido explains.
Photo credit & article inspired by: Massachusetts Institute of Technology
