Breaking and entering: How parasites prepare host cells for invasion

Before the parasite Toxoplasma gondii can invade a cell, it has to know it has reached the right place. New research from the Whitehead Institute reveals that the parasite doesn’t simply recognize a ready-made doorway into the cell. Instead, it helps create the conditions for its own entry.

Researchers in the lab of Whitehead Institute member Sebastian Lourido have discovered that Toxoplasma reorganizes sugar-coated proteins on a host cell’s surface, creating specialized membrane patches that depend on cholesterol and help 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, also an associate professor of biology at MIT.

The study, led by first author Dylan Valleau, appears in The EMBO Journal on Sept. 25.

Knowing when to invade

Toxoplasma gondii is the single-celled parasite that causes toxoplasmosis. It belongs to a larger group of parasites called apicomplexans, which includes Plasmodium, the parasite responsible for malaria, and Cryptosporidium, which causes cryptosporidiosis. These parasites must invade host cells to survive and reproduce. Toxoplasma completes the entire invasion process in less than a minute.

Lourido’s lab has long been interested in a fundamental mystery underlying that process: How does a parasite know when it has reached a host cell and should commit to entering?

A key step in that transition from contact to invasion is the discharge of contents from specialized organelles called rhoptries. At precisely the right moment, Toxoplasma releases their contents into the host cell. Among their cargo are proteins that manipulate the host cell and help establish receptors the parasite uses to enter—in effect, allowing Toxoplasma to make its own doorway.

Scientists had identified several components of the parasite machinery involved in rhoptry discharge, but what tells the parasite when to trigger that machinery remained unclear. The new study provides part of the answer.

Looking at invasion from the host’s side

Rather than searching for additional parasite genes involved in invasion, the researchers approached the question from the other side. They systematically disrupted genes in mammalian host cells and asked which were necessary for Toxoplasma to successfully discharge its rhoptries.

Importantly, the screen focused specifically on rhoptry discharge rather than the broader processes of invasion and replication. That allowed the researchers to home in on host factors involved at the moment the parasite commits to entering.

Two pathways stood out: N-glycosylation, through which complex sugars called glycans are attached to proteins on the cell surface, and production of cholesterol.

At first, cholesterol and glycosylation seemed like two separate leads. As the researchers followed them, however, the pathways converged.

The team identified three Toxoplasma proteins, collectively known as the MIC1/4/6 complex, that recognize particular glycans on the host-cell surface. The parasite proteins appear to gather glycosylated host proteins together, while cholesterol helps make that reorganization possible.

The result, the researchers propose, is a small, specialized region, or microdomain, in the host membrane containing the molecular features needed for rhoptry discharge. In essence, the parasite gathers host-cell components into a spot that creates the right conditions for entry.

When the researchers interfered with formation of that microdomain—by removing host-cell cholesterol, disrupting relevant glycosylation pathways or interfering with the parasite’s ability to recognize the sugars—rhoptry discharge declined and invasion was impaired.

Creating the right signal

The findings may also explain why Toxoplasma doesn’t prematurely fire its invasion machinery whenever it encounters these common sugars.

Glycans are abundant in and around cells. Responding to a single sugar could therefore trigger rhoptry discharge at the wrong time. Requiring the parasite to first cluster glycosylated proteins may provide a more reliable signal that it has made the close contact with a host-cell membrane necessary for successful invasion.

That strategy could also help explain Toxoplasma’s broad range of potential host cells. The sugars recognized by the MIC1/4/6 complex are widely distributed across mammalian tissues, and the complex can recognize more than one glycan type.

The researchers also demonstrated that this newly identified interaction can be disrupted. Adding free sugars that competed with glycans on the host-cell surface inhibited rhoptry discharge. Although the sugars used in the experiments are not potential drugs, the results provide proof of principle that interfering with this host-parasite interface can disrupt invasion.

The findings may extend beyond Toxoplasma. The study suggests the parasite exploits some of the same fundamental features of host-cell membranes used by certain viruses, pointing toward common cellular vulnerabilities that different pathogens may exploit.

For now, the work changes the picture of the host cell’s role in Toxoplasma invasion. Rather than serving as a passive surface waiting for the parasite to find the right receptor, the host membrane is actively reorganized and remodeled by the invader.

By gathering host molecules into just the right arrangement, Toxoplasma appears to create the signal it needs to commit to invasion—effectively preparing its own doorway before stepping through.

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Gaby Clark

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Robert Egan

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