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| https://commons.wikimedia.org/wiki/File%3AJapanese_litter_box.jpg |
Typically
when we think of parasites, we tend to envision razor-mouthed, sci-fi monsters wriggling
around in our intestines, drinking our blood and siphoning off precious
nutrients, causing us to waste away, before our stomachs dramatically burst
open to release more parasite monsters into the world <shudder>. Okay, so I may
have confused human parasites with the title villain of the movie “Alien”. But you get the idea. Becoming infected with something like Toxoplasma gondii, for example, is not
something anybody wants. And in a truly
sinister twist, Toxoplasma is transmitted
by perhaps the cutest and fluffiest of mankind’s best friends: cats (dog
people, please hold the rude comments!).
But some truly weird and wonderful research has shown that a
lab-engineered strain of Toxoplasma may
actually be on its way to becoming a powerful cancer therapeutic.
How do we get Toxo?
What are the risks?
In the early stages of infection with Toxoplasma,
you usually don’t seem sick, save for minor flu-like symptoms. Despite an initial rapid expansion of the
parasite population (the so-called “tachyzoite” stage, tachy- meaning ‘fast’ replication), our immune systems rapidly get
to work eliminating the unwelcome invaders.
But Toxoplasma is tricky, and
hides out in our muscles, eyes, and even brains in a protected form called a
cyst (the “bradyzoite” stage, brady-
meaning ‘slow’ replication). Cysts are
walled-off nodules filled with hundreds of infectious parasites, and can be
nearly 50 µM in diameter- about two-thirds the width of a human hair! And they can hang around in our tissues for
the rest of our lives. In people with
compromised immune systems, like infants, the elderly, people with HIV/ AIDS,
and people who have had a transplant or are being treated with chemotherapy, Toxoplasma can cause a fatal illness
called toxoplasmosis. Toxoplasmosis is characterized by seizures, brain damage, and blindness, can cause birth defects or miscarriage in pregnant women, and has recently been linked to altering its host’s behavior. That’s right folks, it’s a zombie plague! There are even a few rather controversial studies linking Toxoplasma to neurological
disorders such as depression, suicidal ideology and schizophrenia (not to
invoke the trope of the ‘crazy cat lady’ or anything).
Wait, so we want to use
this bad bug as a cancer treatment?!
Yes!! But not quite in its natural, disease-causing
form. One of the things that make
certain cancers so deadly is their ability to hide in plain site by suppressing the body’s immune response, a state called “immune tolerance”. In many cancers, immune cells that should be
activated to fight the tumor have difficulty telling the cancerous cells apart
from normal cells, and instead get shut off. As it turns out, Toxoplasma may contain secret weapons that can be used to turn
immune cells against tumors. Using a
weakened strain of Toxoplasma that
won’t form cysts or cause disease, researchers showed that when they injected
it into cancer-stricken mice, the mouse immune cells were activated and the
tumor cells could suddenly be recognized and attacked. Why is that?
Toxoplasma provokes an inflammatory immune response, which is ideal for fighting
off certain cancers
First
let’s consider what happens in a normal Toxoplasma
infection. The parasite likes to
invade specific cells of the immune system called dendritic cells (DCs) and
macrophages. DCs and macrophages are
what we call “antigen presenting cells” (APCs), since their job is to sample
foreign materials in the body and ring the alarm for the rest of the immune
system by “presenting” a piece of that foreign material, called an antigen, to
other cells. Toxoplasma invasion of these APCs causes them to release a protein called interleukin-12 (IL-12), which transforms plain, old T cells (another
really important cell of the immune system) into specialized Type I helper
cells (TH1), whose job it is to fire up other immune cells such as
cytotoxic T cells (also known as CD8+ T cells), into destroying the
foreign invader. The now activated T
cells multiply like crazy and release another powerful protein called Interferon gamma (IFNγ), the granddaddy of all inflammatory molecules, which
recruit even more immune cells to the fight.
This inflammatory assault forces Toxoplasma
to retreat and form cysts, which is exactly what it needs to do in order to
spread to the next host. So really, you
could think of this as the immune cells playing right into the hands of the
parasite. Clever girl.
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| My cartoon illustrating the immune response to Toxoplasma gondii. The parasites invade APCs (dendritic cell in this example), which release IL-12 and induce T cells to release IFNgamma. |
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| The left panel illustrates immune tolerance. The APCs are able to sample the tumor, but cross-presentation of antigens is impaired. The immune response is suppressed. The right panel illustrates what happens once the APCs have been primed by a Toxo infection. |
Their
theory held water; in one particular study, they injected cps into a mouse model
of lethal ovarian cancer, and APCs that were normally suppressive were
successfully invaded by the parasites and converted into anti-tumor cells. The immune response that followed effectively
attacked tumors and 100 percent of the mice survived! Vaccination was even effective in a
hyper-aggressive model of the disease. What’s
more, it didn’t matter whether the animals had already been exposed to Toxoplasma- good news, since the CDC estimates about 22.5% of Americans 12 years and older have been exposed at some
point. Similarly remarkable results were
seen in models of melanoma and pancreatic cancer, as well. But questions remained about the exact
mechanisms at play, what parasite factors were responsible for triggering which
immune cells, and whether this treatment could be safe for humans.
The
latest paper from the Dartmouth group published just last week in PLoS Genetics
has begun to fill in some of the holes, exploring which Toxoplasma proteins are critical for orchestrating the anti-tumor
response. They selectively deleted individual
proteins from the latest-generation parasite vaccine strain genome and then looked
at whether the altered parasite could still trigger a potent immune response. So far they’ve found that live, invasive
parasites are absolutely required to elicit the immune response. And an important parasite structure called
the parasitophorous vacuolar membrane (PVM), along with several, specific parasite
factors secreted before and during invasion, is also key. Another cool upshot of this work is that they
have been able to use Toxoplasma as a
tool to better understand the behavior and function of the immune cells, which
is a very valuable contribution to cancer immunotherapy in its own right.
So is this treatment ready
for prime time?
Not
just yet. The work has only been done in
mice, which of course may or may not translate well to humans. And a ton of safety studies would need to be
carried out to ensure the Toxoplasma
vaccine strain is not dangerous in any way before we can start treating cancer
patients with a live parasite. But the use
of Toxoplasma in a clinical context,
and the immunological knowledge gained from these studies, represents a
promising new avenue for therapy, and I for one, will be following it with
great interest.
The TL/DR Version:
Scientists
have cured several mouse tumors by infecting the mice with a safe, non
disease-causing vaccine strain of Toxoplasma
gondii, a parasite commonly found in cat poo. Toxo
triggers the right kind of immune response for fighting tumors, in cancers
where the immune cells are normally suppressed.
The treatment works even if the mice already have pre-existing immunity
to Toxo. The latest research has identified which
parasite proteins are critical to induce a potent anti-tumor response.
*Note that you are
more likely to become infected by eating the cyst-laden meat of under cooked
lamb or pork, so it’s not all the cat’s fault.
