Before the parasite Toxoplasma gondii can successfully invade a host cell, it must determine that it has reached the correct location. According to new research from the Whitehead Institute published in The EMBO Journal, the parasite does not merely locate a ready-made doorway. Instead, it actively helps create the conditions necessary for its own entry by reorganizing sugar-coated proteins on the surface of the host cell in a cholesterol-dependent manner.
How Toxoplasma Remodels Host Cell Surfaces for Invasion
Researchers in the lab of Whitehead Institute Member Sebastian Lourido discovered that this process forms specialized membrane patches that trigger the parasite’s invasion machinery. The host cell, far from being a kind of passive, static entity in this process, is actually having its surface mixed around and remodeled by the parasite in order to achieve the right conditions for entry,
said Lourido, who is also an associate professor of biology at MIT, as reported by News Medical. The study was led by first author Dylan Valleau.
Triggering the Parasite’s Invasion Machinery
Toxoplasma gondii is a single-celled parasite responsible for toxoplasmosis and belongs to the apicomplexan group, which also includes the organisms that cause malaria and cryptosporidiosis. To survive and reproduce, these parasites must invade host cells. A critical step in this transition from initial contact to entry involves discharging specialized organelles known as rhoptries. At the precise moment of entry, Toxoplasma releases its contents into the host cell. The cargo includes proteins that manipulate the host and establish receptors utilized by the parasite to enter, effectively allowing Toxoplasma to construct its own doorway.
While scientists had previously identified several components of the parasite machinery responsible for rhoptry discharge, what signals the parasite to trigger that machinery remained unclear. To investigate this from the host’s side rather than searching exclusively for additional parasite genes, the researchers systematically disrupted genes in mammalian host cells to determine which ones were necessary for successful rhoptry discharge.
The Role of Glycans and Cholesterol in Microdomain Formation
The screen identified three Toxoplasma proteins—collectively known as the MIC1/4/6 complex—that recognize specific glycans on the surface of the host cell. These parasite proteins gather glycosylated host proteins together, while cellular cholesterol facilitates the reorganization. This creates a small, specialized microdomain in the host membrane that contains the molecular features required for rhoptry discharge.
When the researchers interfered with this microdomain formation by removing host-cell cholesterol, disrupting relevant glycosylation pathways, or impairing the parasite’s ability to recognize the sugars, rhoptry discharge declined and invasion was hindered. Because glycans are abundant in and around cells, responding to a single sugar could otherwise trigger premature discharge. Requiring the parasite to cluster glycosylated proteins first provides a more reliable signal of close membrane contact, a strategy that may also help explain the broad range of potential host cells that Toxoplasma can infect.
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