Researchers from the Johns
Hopkins Bloomberg School of Public Health and other
institutions have discovered how Toxoplasma gondii —
an opportunistic parasite that causes toxoplasmosis and is
responsible for damage to the brain, eyes and other organs
— interacts with its host cell.
Rather than examine Toxoplasma as a parasite in and of
itself, Isabelle Coppens, lead author of the study, and her
colleagues set out to understand how it successfully
obtains essential host nutrients, including cholesterol,
which it needs to rapidly multiply. This is the first known
study of its kind to examine Toxoplasma in this way. The
study is published in the April 21 issue of the journal
Cell.
Behind Salmonella and Listeria, Toxoplasma is the third
most common cause of food-related deaths in the United
States, affecting 60 million people in this country alone.
Infections occur from accidentally swallowing cat feces
from a Toxoplasma-infected cat, drinking from contaminated
water or eating tainted raw or undercooked meat. More than
50 percent of the world's population is infected with the
Toxoplasma parasite, although very few people show the
flulike symptoms because a healthy person's immune system
usually keeps the parasite from causing illness. However,
pregnant women and individuals with compromised immune
systems can be more susceptible to infection, according to
the Centers for Disease Control and Prevention. Toxoplasma
may also contribute to some cases of schizophrenia.
In order to survive in the human body, Toxoplasma needs to
invade a host cell and multiply inside a vacuole, which is
a self-made capsule, said Coppens, who is an assistant
professor in the Bloomberg School's
Department of Molecular Microbiology and Immunology. To
satisfy its rapid growth, the parasite consumes the host
cell's resources, which it gets from its digestive
compartments (lysosomes). Toxoplasma is not able to
synthesize many essential molecules, making its survival
dependent on the host cell.
The study authors spent the last eight years examining
Toxoplasma genes involved in nutrient acquisition. They
discovered that the parasite essentially hijacks the
microtubule organizing center of the cell, which controls
cell architecture, movement and division. The parasite uses
the microtubule organizing center to create pathways into
the cell in order to attract lysosomes closer to its
vacuole. The parasite then secretes a protein that cuts off
the lysosome's pathway into the cell, in essence trapping
the lysosome inside the vacuole. Lipids, amino acids,
sugars and metals, which are food for the parasite, then
escape from the lysosome through small pores and nourish
the parasite, which allows it to multiply, sometimes
doubling in quantity every eight hours.
"Now that we know how the parasite obtains a large variety
of nutrient molecules from the host lysosomes, our goal is
to disrupt the series of events that allow it to take in
nutrients, which will essentially starve the parasite to
death," Coppens said.
The host cell's response to cholesterol sequestration by
the parasite has important implications in understanding
cholesterol equilibrium in our cells. The work being done
on Toxoplasma by Coppens and her co-authors may offer new
perspectives for understanding cholesterol trafficking
inside cells, and therefore atherosclerosis, which is
caused by plaque that builds up in arteries. Symptoms from
atherosclerosis include reduced blood flow in arms, legs
and arteries, which can lead to poor circulation, stroke or
heart attack. By 2020, it is expected to be the No. 1 cause
of death worldwide.
Atherosclerosis is linked to high blood cholesterol, which
results from a mismatch between cholesterol synthesis,
dietary intake and storage within cells. The work of
Coppens with Toxoplasma provides new insights into the
mechanisms by which human cells process and store
cholesterol, in this case in response to a parasite
infection.
Additionally, deciphering the ways by which the parasite
takes over the host cell's microtubule organizing center,
which results in arrest in host cell division, is a
promising area of research. It may contribute to a better
understanding of the regulation of the microtubule
organizing center function, which is required for better
development of anti-cancer treatment strategies.
Additional authors of the study are Joe Dan Dunn, Julia D.
Romano, Marc Pypaert, Hui Zhang, John C. Boothroyd and
Keith A. Joiner.
The study was supported by grants from the American Heart
Association, National Institutes of Health, Howard Hughes
Medical Institute and Burroughs Wellcome Fund.
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