Faculty Member

Sebastian
Lourido

Whitehead Member Sebastian Lourido

SEBASTIAN LOURIDO

Member, Whitehead Institute

617.324.4920
lourido@wi.mit.edu

LOURIDO LAB

LOURIDO
PUBLICATIONS

As an undergraduate at Tulane University, Sebastian Lourido was of two minds: one artistic and the other scientific. “I was a visual artist—a painter and print-maker—who was fascinated by the systems and structures that make up biological life,” he recalls. “For a while, these seemed like divergent paths. But the more science I learned, the more I saw the creativity embodied in it. And, eventually, I realized that a career as a research scientist offered much of the creativity I had sought through the arts.”

Today, that merging of the technical with the creative has brought him to a unique place: studying Toxoplasma gondii, a single-celled parasite that infects an estimated 25% of the world’s population and can cause serious disease in pregnant women, infants, and immunocompromised patients. Specifically, Lourido focuses on how T. gondii invades host cells and establishes its site of replication. The work holds great promise for exposing treatable vulnerabilities in the parasite—and in other closely related parasites: Plasmodium spp., which cause malaria and contribute to more than a million deaths each year and Cryptosporidium spp., which cause cryptosporidiosis, a gastrointestinal illness that can be fatal in those with a compromised immune system.

Lourido’s lab is interested in the molecular events that enable these apicomplexan parasites to remain widespread and deadly infectious agents for diverse animal hosts. Lourido uses T. gondii to model features conserved throughout this group, such as their reliance on calcium signaling to regulate movement. He combines several approaches to investigate the unique biology of these organisms. His lab’s work seeks to expand our understanding of nature’s diversity and identify specific features that can be targeted to treat parasite infections.

Calcium Signaling

Changes in calcium levels within a cell regulate cellular responses as diverse as membrane repair and muscle contraction. In apicomplexan parasites, calcium regulates movement in part through the regulation of two processes: release of the proteins that bind to surfaces and host cells, and regulation of the motors that power motility. Lourido seeks to understand the molecular details of these processes, examining both the events that lead to calcium changes within the cell and the signaling events that follow them.

Protein Kinases

Lourido is interested in how calcium signals are decoded by enzymes, called kinases, which modify and change the activity of other proteins. In particular, his lab studies the role of calcium-dependent protein kinases (CDPKs) as the primary calcium-responsive kinases in parasites. His lab’s work, and that of many others, has defined diverse roles for these kinases in regulating important events during the life cycle of apicomplexans. He has recently used a novel alpaca-derived molecular probe to investigate the structure of CDPKs, defining a new way of preventing the enzyme from working. His lab continues to develop biochemical methods to study these kinases, in addition to chemical-genetic approaches to study their function in vivo.

Chemical Genetics

The Lourido lab engineered a panel of strains to study individual CDPKs. This approach relies on mutating the “gatekeeper” residue that restricts the depth of a specific pocket in the surface of these enzymes. This allows his lab members to specifically inhibit or identify the targets of individual kinases. Using this approach, the lab has previously teased apart the distinct roles of two CDPKs as T. gondii bursts from the host cell. They continue to investigate the functions of these and other CDPKs and aim to identify specific kinase targets.

Genome Engineering

Much of Lourido’s work is made possible through a variety of genome-engineering methods. His lab is interested in developing new methods to enable efficient functional analysis of parasite genes, including the different versions of these genes. The Lourido lab was among the first to adapt CRISPR/Cas9 to engineer the T. gondii genome, and their plasmids are available to anyone through the Addgene repository. They continue to improve these systems to enable genome-scale screening in parasites, which will allow exploration of the multitude of apicomplexan genes with unknown functions.

SELECTED ACHIEVEMENTS

  • DBBS Scholars Award, Washington University, Saint Louis, MO (2006)
  • Molecular Cellular and Immunoparasitology Scientific Award (2008)
  • Molecular Cellular and Immunoparasitology Scientific Award (2011)
  • Spencer T. and Ann W. Olin Fellowship, Washington University, Saint Louis, MO (2012)
  • NIH Director's Early Independence Award (2013)

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