Science1 publisher2 min readPublished
Toxoplasma rearranges the host cell surface to trigger its own invasion
Whitehead Institute researchers report that Toxoplasma gathers the host's sugar-coated proteins into cholesterol-dependent patches that trigger its own entry. Blocking those patches impaired invasion, so the host membrane becomes a candidate drug target.
The Scientist · Science desk
What happened
- Whitehead Institute researchers found that Toxoplasma gathers the host cell's sugar-coated surface proteins into small, cholesterol-dependent patches that help trigger the machinery it uses to force its way in.
- Rather than hunt for more parasite genes, the team disrupted genes in mammalian host cells and asked which ones the parasite needed to discharge its invasion organelles, the rhoptries.
- Two host processes proved necessary and turned out to be connected: attaching complex sugars to surface proteins, and producing cholesterol.
- Removing host cholesterol, disrupting the sugar attachment, or blocking the parasite's recognition of the sugars each cut rhoptry discharge and impaired invasion.
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Why it matters
- capability Because the parasite needs host cholesterol and glycosylation to get in, the cell's own membrane, not only the parasite's proteins, becomes a place to block invasion.
- exposure Toxoplasma shares its host-invasion strategy with the malaria and cryptosporidiosis parasites, so a host-side vulnerability found here could reach across the family.
- constraint The work was done in cultured mammalian cells and tracked only rhoptry discharge, so it cannot say a host-membrane drug would help a patient or stop malaria.
The screen deliberately measured one step, not the whole invasion [8]. The rhoptries are the organelles whose discharge commits the parasite to entering, so the team looked only at what the host needed for them to fire [6]. That focus isolated the factors that matter at the moment of commitment, and set aside the noise of full invasion and replication [8].
Three parasite proteins came out of that search [10]. The MIC1/4/6 complex recognizes particular glycans on the host surface and pulls the sugar-coated proteins together, and cholesterol makes the gathering possible [10]. The result is a microdomain, a small region of host membrane carrying the molecular features rhoptry discharge requires [11].
The clustering may also keep the parasite from firing too early [13]. Glycans are common in and around cells, so reacting to a single sugar would trigger discharge at the wrong moment [13]. Bunching glycosylated proteins together is a more reliable sign that the parasite has pressed against a host membrane [13].
"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 Sebastian Lourido, whose lab did the work and who is an associate professor of biology at MIT [14][2].
Toxoplasma completes the whole invasion in under a minute, and it is one of the apicomplexans, a group that includes Plasmodium, the malaria parasite, and Cryptosporidium [5][4]. All of them must invade host cells to survive and reproduce [4]. If entry depends on a feature of the host membrane, that feature is something a drug could aim at [12]. The screen ran in mammalian cells in culture and tracked rhoptry discharge, so it does not show that touching the host membrane would help a patient or work against malaria [8][7]. The study, led by first author Dylan Valleau, appears in The EMBO Journal on September 25 [3].
What to watch
- Whether Plasmodium or Cryptosporidium require the same glycan clustering and cholesterol microdomain to invade.
- Whether interfering with host cholesterol or glycosylation impairs infection in an animal model, not just cultured cells.
- Identification of the specific host glycans and receptors the MIC1/4/6 complex recognizes.