Perhaps a bit lengthy, but a great overview of toxoplasmosis and its misconceptions by Dr. Janet L. Swanson, Director of Shelter Medicine, Maddie’s Shelter Medicine Program, Cornell University College of Veterinary Medicine reviews. Well worth the time.
Toxoplasma keeps the immune response low enough so that it can thrive, but high enough so that its human hosts generally live healthy lives and can incubate parasites.
The parasite Toxoplasma gondii is a silent success. It infects up to 95% of people in many regions of the world, and most of them never know it, due to the parasite’s artful manipulation of its host’s immune response. Toxoplasma keeps the immune response low enough so that it can thrive, but high enough so that its human hosts generally live healthy lives and can incubate parasites. Scientists at EMBL and the Institute for Advanced Biosciences (IAB, an INSERM – CNRS – Université Grenoble-Alpes research centre) have uncovered one of the ways it maintains this balance, in a paper published today in Structure.
“The parasite rewires the host’s inflammatory response,” says Matthew Bowler, who led the research at EMBL. “It completely subverts the chain reaction that would normally trigger our body’s defenses.”
When a cell in your body detects a parasite, it sets off a chain reaction. Inside that cell, a series of molecules activate each other until a protein called p38α is activated and moves into the cell’s nucleus. There, it turns on the genes that trigger the inflammatory response. Among other things, the purpose of that response is to eliminate the pathogen. One would expect parasites like Toxoplasma to want to subdue that response, but Mohamed-Ali Hakimi and colleagues at IAB discovered a few years ago that Toxoplasma secretes a protein, GRA24, which does just the opposite: it activates and controls our inflammatory response.
Bowler and Hakimi discovered that GRA24 bypasses the cell’s chain reaction, activating p38α directly, and pulling it into the nucleus to turn on inflammatory response genes. Using a combination of techniques, they found that the Toxoplasma protein attaches itself much more strongly to p38α than the cell’s own proteins do. So by producing a protein that binds directly, and very tightly, to p38α, Toxoplasma controls the level of the inflammatory response and sustains it by making it inaccessible to the proteins that would usually turn it off. This is why Toxoplasma isn’t considered a serious health threat except for pregnant women and people with compromised immune systems.
This research has generated a new way to assess the efficacy of anti-inflammatory drugs, many of which are designed to block p38α. So far it has been difficult to assess how effective they are, because scientists haven’t had a good way to produce an active form of p38α in the lab. In producing GRA24 bound to p38α, Bowler, Hakimi and colleagues – with the help of EMBL’s Protein Expression and Purification Core Facility – created just that. The tight interaction with the parasite protein keeps p38α in its active state, so researchers can now subject it to the drugs they’d like to test, and evaluate how well they block p38α’s active site, which the Toxoplasma protein doesn’t interfere with.
Read more at: https://phys.org/news/2016-11-toxoplasma.html#jCp
T. gondii hides in vacuoles, but the immune system knows it’s there.
Scientists at the Francis Crick Institute have discovered how the host immune system deals with the prolific Toxoplasma parasite as it attempts to camouflage itself by hiding inside a capsule called a vacuole in human cells.
For the first time, they’ve revealed how a protein called ubiquitin tags the vacuole hiding Toxoplasma. The cell’s acidification system then destroys it.
Eva Frickel, the research group leader at the Crick who led the work, explains: “The parasite Toxoplasma gondii resides inside a vacuole in the cells of the organism it infects. The vacuole provides a safe haven for the parasite where it can multiply and cause damage to the host. Until now, it was unclear what defence mechanisms human cells deploy to the vacuole to clear and eliminate Toxoplasma. We have found that a human protein called ubiquitin tags the vacuole for destruction via the cell’s acidification system.”
Toxoplasma gondii is a parasite found almost everywhere. It is in soil and unwashed food, but its most important host is the cat. It causes an infection called toxoplasmosis that can cause miscarriage and is especially damaging to people who have a weakened immune system, others never know they’ve been infected.
The team used immunofluorescent microscopy to visualise each step in vacuole destruction. They learnt how a ubiquitin protein tags the vacuole and then attracts other proteins that stick on and allow it to join with an acidic compartment called the lysosome. This then destroys the vacuole and parasite.
“This work is the first demonstration of how ubiquitin tagging leads to vacuole-lysosome fusion in human cells infected with Toxoplasma,” Eva says. “Until now, it was thought the vacuoles were not susceptible. Mouse studies have shown a different route to fusion between the vacuole and lysosome. This raises questions for further studies on how vacuolar-lysosomal fusion in human cells happens and why the human cellular immune response is different from the mouse.”
Eva’s research team explores how human cells react to Toxoplasma and what it is that makes it one of the most successful parasites on the planet. There is no vaccine to protect against Toxoplasma infection or medicine that kills the parasite.
Eva talks about their work and shares images from the progress they are making in research in the Crick’s first public exhibition (above). How do we look? is a collection of scientific images that could be mistaken for works of art though each has been created by a scientist to solve a research problem.
See original article here.
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