Toxoplasma remodels host cell surfaces to trigger invasion

"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.

Knowing when to invade

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?

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

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 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

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.

The researchers additionally 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.

Source:

Whitehead Institute for Biomedical Research

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