University of Michigan researchers have discovered that a common parasite infecting one in five Americans needs an escape hatch to go on a destructive mission that can damage the brain, eyes and other organs.
The protozoan parasite called Toxoplasma gondii infects up to 23 percent of Americans. In some areas of the world, up to 95 percent of the population serves as host to this parasite, which causes toxoplasmosis, a serious infection that can lead to birth defects, eye disease and life-threatening encephalitis.
In the study published in the current issue of Science, UM researchers report the protein called TgPLP1 is responsible for helping the parasite spread infection. This research breakthrough may one day aid in developing drugs or vaccines to treat or prevent toxoplasmosis or related diseases, including malaria.
“For some time we've been interested in how this parasite successfully enters cells,” says Vern B. Carruthers, Ph.D., the study’s senior author and associate professor in the Department of Microbiology and Immunology at the U-M Medical School.
“A couple of years ago, we identified several new proteins secreted by the parasite. Among these was TgPLP1, which captured our interest because it is related to proteins of our own immune system responsible for warding off infection and cancer," Carruthers says.
After the initial period of infection, which may cause mild flu-like symptoms, Toxoplasma gondii goes on to lie dormant in a person's brain and central nervous system. But if a person's immune system becomes compromised, such as from human immunodeficiency virus (HIV) infection or organ transplant surgery, the Toxoplasma infection can be reactivated.
In an immunocompromised person, Toxoplasma gondii amplifies the infection by invading a cell and undergoing several rounds of replication within that cell. "Then it has to escape from the cell in order to find and infect additional cells," Carruthers explains.
TgPLP1 is a type of protein responsible for forming pores, or small openings, in the cell membrane to allow the parasite to escape and cause disease more rapidly throughout the host.
Carruthers' research team pinpointed how TgPLP1 works by generating and observing a cultured parasite that does not have the TgPLP1 protein. While observing the movements of the mutant parasite with video microscopy, the team noticed that, compared to the normal parasite, the parasite without TgPLP1 struggled to get out of the host cells and remained trapped within the cell membrane.
The research team offers several theories as to how the protein enhances the parasite's ability to cause disease.
“We think that this protein helps the parasite escape by weakening the membranes that encase the parasite during replication,” says Bjorn F.C. Kafsack, Ph.D., a research fellow in U-M’s Department of Microbiology and Immunology and the study’s first author. “It’s also possible that TgPLP1 works by allowing other proteins to break out ahead of the parasite. These other proteins could digest components of the host cell that serve as barriers to the parasite getting out of the host cell.”
Even when infected host cells were treated with a drug that would normally trigger the parasite to leave, TgPLP1-deficient parasites had difficulty or failed to exit from the host cell.
For the next stage of the research, the team injected mice with the TgPLP1-deficient parasites. "The mutant parasites grow quite quickly when we culture them in the lab but when we infect mice with them, they're severely weakened," a fact that came as a surprise, Kafsack says.
Significantly more TgPLP1-deficient parasites were needed to cause disease in the mice, compared to the normal parasites, researchers found.
“It implies that the ability of the parasite to quickly escape from its old host cell is a critical step during infection of animals,” Kafsack says.
Now that researchers know the purpose and importance of this protein for the disease, they may find ways of interfering with its functions, such as finding a selective treatment that disables the parasite protein and therefore slows or stops Toxoplasma gondii's spread.
Using the gene-deleted mutants developed in this research against Toxoplasma gondii, scientists may eventually be able to develop a vaccine against this common infection, Carruthers says.
"Because the gene deletion mutants are so weakened, they could be used as a vaccine strain to initiate an immune response that may be protective, but without persisting or causing disease as the normal parasites would," Carruthers says.
This research may also offer insights into how the parasite that causes malaria, which kills more than 1 million people each year, might spread and cause infection.
"Because the malaria parasite has proteins similar to the one in the study, it may also use a pore-forming protein to escape from infected red blood cells," Carruthers says. Better understanding these mechanisms may someday help researchers develop new strategies for controlling the spread of the disease.
Funding for the research came from the National Institutes of Health and the American Heart Association.
Citation: Science, Vol. 323, No. 5913, pp. 530-533.
Written by Kim Roth
Shantell M. Kirkendoll | University of Michigan
Further reports about: > Immunology > TgPLP1 > TgPLP1-deficient > Toxoplasma > Toxoplasma gondii > birth defect > birth defects > blood cell > cell membrane > common parasite infecting > eye disease > host cells > immune system > life-threatening encephalitis > parasite spread infection > protozoan parasite > toxoplasmosis
The personality factor: How to foster the sharing of research data
06.09.2017 | ZBW – Leibniz-Informationszentrum Wirtschaft
Europe’s Demographic Future. Where the Regions Are Heading after a Decade of Crises
10.08.2017 | Berlin-Institut für Bevölkerung und Entwicklung
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
22.09.2017 | Life Sciences
22.09.2017 | Medical Engineering
22.09.2017 | Physics and Astronomy