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“Parasites, Mew Give Me Road Rage”

Taken from New Scientist, April 2, 2016.
Cats can make us angry. Scratching our furniture, waking us up – and giving us parasites that may cause explosive rage.

Toxoplasma gondii is a parasite carried by cats that lives in the brains of as many as a third of all people worldwide. Now the parasite has been linked to a psychiatric condition involving disproportionate outbursts of aggression, like road rage. Emil Coccaro at the University of Chicago thinks the parasite may be altering neurotransmitters in the brain.

People with rage disorder twice as likely to have latent toxoplasmosis parasite infection

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People with rage disorder twice as likely to have latent toxoplasmosis parasite infection

New study identifies link between Intermittent Explosive Disorder and exposure to the common toxoplasma gondii parasite typically found in undercooked meat, cat feces…

Date: March 23, 2016

Source: University of Chicago Medical Center

Summary:

Individuals with a psychiatric disorder involving recurrent bouts of extreme, impulsive anger — road rage, for example — are more than twice as likely to have been exposed to a common parasite than healthy individuals with no psychiatric diagnosis. In a study involving 358 adult subjects, researchers found that toxoplasmosis, a relatively harmless parasitic infection carried by an estimated 30 percent of all humans, is associated with intermittent explosive disorder and increased aggression.

FULL STORY
Individuals with a psychiatric disorder involving recurrent bouts of extreme, impulsive anger–road rage, for example–are more than twice as likely to have been exposed to a common parasite than healthy individuals with no psychiatric diagnosis.

In a study involving 358 adult subjects, a team led by researchers from the University of Chicago found that toxoplasmosis, a relatively harmless parasitic infection carried by an estimated 30 percent of all humans, is associated with intermittent explosive disorder and increased aggression.

The findings are published in the Journal of Clinical Psychiatry on March 23, 2016.

“Our work suggests that latent infection with the toxoplasma gondii parasite may change brain chemistry in a fashion that increases the risk of aggressive behavior,” said senior study author Emil Coccaro, MD, Ellen. C. Manning Professor and Chair of Psychiatry and Behavioral Neuroscience at the University of Chicago.

“However, we do not know if this relationship is causal, and not everyone that tests positive for toxoplasmosis will have aggression issues,” Coccaro said, adding that additional studies are needed.

Intermittent explosive disorder (IED) is defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, as recurrent, impulsive, problematic outbursts of verbal or physical aggression that are disproportionate to the situations that trigger them. IED is thought to affect as many as 16 million Americans, more than bipolar disorder and schizophrenia combined.

As part of their pioneering research to improve diagnosis and treatment for IED and impulsive aggression, Coccaro and his colleagues examined possible connections to toxoplasmosis, an extremely common parasitic infection. Transmitted through the feces of infected cats, undercooked meat or contaminated water, toxoplasmosis is typically latent and harmless for healthy adults. However, it is known to reside in brain tissue, and has been linked to several psychiatric diseases, including schizophrenia, bipolar disorder and suicidal behavior.

The research team recruited 358 adult subjects from the U.S., who were evaluated for IED, personality disorder, depression and other psychiatric disorders. Study participants were also scored on traits including anger, aggression and impulsivity. Participants fell into one of three groups. Roughly one third had IED. One third were healthy controls with no psychiatric history. The remaining third were individuals diagnosed with some psychiatric disorder, but not IED. This last group served as a control to distinguish IED from possible confounding psychiatric factors.

Hold your cats

The research team found that IED-diagnosed group was more than twice as likely to test positive for toxoplasmosis exposure (22 percent) as measured by a blood test, compared to the healthy control group (9 percent).

Around 16 percent of the psychiatric control group tested positive for toxoplasmosis, but had similar aggression and impulsivity scores to the healthy control group. IED-diagnosed subjects scored much higher on both measures than either control group.

Across all study subjects, toxoplasmosis-positive individuals scored significantly higher on scores of anger and aggression. The team noted a link between toxoplasmosis and increased impulsivity, but when adjusted for aggression scores, this link became non-significant. This finding suggests toxoplasmosis and aggression are most strongly correlated.

However, the authors caution that the study results do not address whether toxoplasmosis infection may cause increased aggression or IED.

“Correlation is not causation, and this is definitely not a sign that people should get rid of their cats,” said study co-author Royce Lee, MD, Associate Professor of Psychiatry and Behavioral Neuroscience at the University of Chicago. “We don’t yet understand the mechanisms involved–it could be an increased inflammatory response, direct brain modulation by the parasite, or even reverse causation where aggressive individuals tend to have more cats or eat more undercooked meat. Our study signals the need for more research and more evidence in humans.”

Coccaro and his team are now further examining the relationship between toxoplasmosis, aggression and IED. If better understood, this connection may inform new strategies to diagnose or treat IED in the future.

“It will take experimental studies to see if treating a latent toxoplasmosis infection with medication reduces aggressiveness,” Coccaro said. “If we can learn more, it could provide rational to treat IED in toxoplasmosis-positive patients by first treating the latent infection.”

Story Source:

The above post is reprinted from materials provided by University of Chicago Medical Center. The original item was written by Kevin Jiang.Note: Materials may be edited for content and length.

Journal Reference:

  1. Emil F. Coccaro, Royce Lee, Maureen W. Groer, Adem Can, Mary Coussons-Read, Teodor T. Postolache. Toxoplasma gondiiInfection.The Journal of Clinical Psychiatry, 2016; 334 DOI:4088/JCP.14m09621

 

Documented Toxoplasmosis Changes Behaviors – Update

Researchers from the Centre d’Écologie Fonctionnelle et Évolutive (CNRS/Université de Montpellier/Université Paul Valéry Montpellier 3/EPHE) have shown that chimpanzees infected with toxoplasmosis are attracted by the urine of their natural predators, leopards, but not by urine from other large felines. The study, published on 8 February 2016 in Current Biology, suggests that parasite manipulation by Toxoplasma gondii is specific to each host. It fuels an ongoing debate on the origin of behavioral modifications observed in humans infected with toxoplasmosis: they probably go back to a time when our ancestors were still preyed upon by large felines.

Parasites such as those that cause toxoplasmosis take various pathways, some of them complex, in order to develop into their adult form and reproduce in a so-called definitive host. These pathways may include stages consisting in the infection of an intermediary host. In order to pass from one such host to another, some parasites are able to induce behavioral changes in their hosts. However, this process, known as parasite manipulation, is rarely observed in mammals.

The agent of toxoplasmosis, Toxoplasma gondii, is an exception. This protozoan, which infects a wide range of species including humans, can only reproduce in felines, which become infected by ingesting a parasitized prey. Studies on mice have shown that this parasite induces olfactory modifications in parasitized rodents: unlike healthy individuals, parasitized mice appear to be attracted by the odor of cat urine, thus making it more likely for the parasite that its intermediate hosts, mice, are eaten by cats, a definitive feline host. In humans, other studies have shown changes in behavior in parasitized individuals, such as personality changes, prolonged reaction times and reduced long-term concentration. However, no beneficial effects for the parasite have been observed, since modern humans are no longer hunted by felines.

In order to understand the origin of such behavioral change in humans, the researchers performed behavioral tests based on olfactory cues on chimpanzees, humans’ closest relatives, which are still preyed upon in their natural environment by a feline: the leopard. The tests showed that, whereas uninfected individuals avoided leopard urine, parasitized individuals lost this aversion. More surprisingly, this behavioral modification is not observed when parasitized chimpanzees are exposed to the urine of felines (lions and tigers) that are not their natural predators, thus suggesting that parasite manipulation induced by Toxoplasma gondii is highly specific.

These findings fuel an ongoing debate on the origin of behavioral and olfactory modifications observed in humans: rather than being simple secondary effects of toxoplasmosis, such modifications probably go back to a time when our ancestors were still preyed upon by large felines. In addition to chimpanzees, the researchers now hope to focus on a wider range of species undergoing different predation pressures, so as to shed light on the evolutionary history of Toxoplasma gondii and unravel the circumstances under which the parasite manipulates its hosts.

Scientist Discover New, Easier System to Alter DNA!

DNA illustration (stock image). CRISPR sequences were first described in 1987 and their natural biological function was initially described in 2010 and 2011. The application of the CRISPR-Cas9 system for mammalian genome editing was first reported in 2013, by Zhang and separately by George Church at Harvard.
Credit: © Denys Rudyi / Fotolia

A team including the scientist who first harnessed the revolutionary CRISPR-Cas9 system for mammalian genome editing has now identified a different CRISPR system with the potential for even simpler and more precise genome engineering.

In a study published in Cell, Feng Zhang and his colleagues at the Broad Institute of MIT and Harvard and the McGovern Institute for Brain Research at MIT, with co-authors Eugene Koonin at the National Institutes of Health, Aviv Regev of the Broad Institute and the MIT Department of Biology, and John van der Oost at Wageningen University, describe the unexpected biological features of this new system and demonstrate that it can be engineered to edit the genomes of human cells.

“This has dramatic potential to advance genetic engineering,” said Eric Lander, Director of the Broad Institute and one of the principal leaders of the human genome project. “The paper not only reveals the function of a previously uncharacterized CRISPR system, but also shows that Cpf1 can be harnessed for human genome editing and has remarkable and powerful features. The Cpf1 system represents a new generation of genome editing technology.”

CRISPR sequences were first described in 1987 and their natural biological function was initially described in 2010 and 2011. The application of the CRISPR-Cas9 system for mammalian genome editing was first reported in 2013, by Zhang and separately by George Church at Harvard.

In the new study, Zhang and his collaborators searched through hundreds of CRISPR systems in different types of bacteria, searching for enzymes with useful properties that could be engineered for use in human cells. Two promising candidates were the Cpf1 enzymes from bacterial species Acidaminococcus and Lachnospiraceae, which Zhang and his colleagues then showed can target genomic loci in human cells.

“We were thrilled to discover completely different CRISPR enzymes that can be harnessed for advancing research and human health,” Zhang said.

The newly described Cpf1 system differs in several important ways from the previously described Cas9, with significant implications for research and therapeutics, as well as for business and intellectual property:

  • First: In its natural form, the DNA-cutting enzyme Cas9 forms a complex with two small RNAs, both of which are required for the cutting activity. The Cpf1 system is simpler in that it requires only a single RNA. The Cpf1 enzyme is also smaller than the standard SpCas9, making it easier to deliver into cells and tissues.
  • Second, and perhaps most significantly: Cpf1 cuts DNA in a different manner than Cas9. When the Cas9 complex cuts DNA, it cuts both strands at the same place, leaving ‘blunt ends’ that often undergo mutations as they are rejoined. With the Cpf1 complex the cuts in the two strands are offset, leaving short overhangs on the exposed ends. This is expected to help with precise insertion, allowing researchers to integrate a piece of DNA more efficiently and accurately.
  • Third: Cpf1 cuts far away from the recognition site, meaning that even if the targeted gene becomes mutated at the cut site, it can likely still be re-cut, allowing multiple opportunities for correct editing to occur.
  • Fourth: the Cpf1 system provides new flexibility in choosing target sites. Like Cas9, the Cpf1 complex must first attach to a short sequence known as a PAM, and targets must be chosen that are adjacent to naturally occurring PAM sequences. The Cpf1 complex recognizes very different PAM sequences from those of Cas9. This could be an advantage in targeting some genomes, such as in the malaria parasite as well as in humans.

“The unexpected properties of Cpf1 and more precise editing open the door to all sorts of applications, including in cancer research,” said Levi Garraway, an institute member of the Broad Institute, and the inaugural director of the Joint Center for Cancer Precision Medicine at the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and the Broad Institute. Garraway was not involved in the research.

Zhang, Broad Institute, and MIT plan to share the Cpf1 system widely. As with earlier Cas9 tools, these groups will make this technology freely available for academic research via the Zhang lab’s page on the plasmid-sharing-website Addgene, through which the Zhang lab has already shared Cas9 reagents more than 23,000 times to researchers worldwide to accelerate research. The Zhang lab also offers free online tools and resources for researchers through its website, http://www.genome-engineering.org.

The Broad Institute and MIT plan to offer non-exclusive licenses to enable commercial tool and service providers to add this enzyme to their CRISPR pipeline and services, further ensuring availability of this new enzyme to empower research. These groups plan to offer licenses that best support rapid and safe development for appropriate and important therapeutic uses. “We are committed to making the CRISPR-Cpf1 technology widely accessible,” Zhang said.

“Our goal is to develop tools that can accelerate research and eventually lead to new therapeutic applications. We see much more to come, even beyond Cpf1 and Cas9, with other enzymes that may be repurposed for further genome editing advances.”


Story Source:

The above post is reprinted from materials provided by Broad Institute of MIT and Harvard. Note: Materials may be edited for content and length.


Journal Reference:

  1. Zetsche et al. Cpf1 Is a Single RNA-Guided Endonuclease of a Class 2 CRISPR-Cas System. Cell, September 2015 DOI:10.1016/j.cell.2015.09.038

 

Parasites Practicing Mind Control

T gondii Cell

T. gondii Cell

A microscopic cyst in the brain of a mouse containing thousands of Toxoplasma gondiiparasites. New research has found that the parasite is able to exert a form of mind control by turning its host’s genes on and off. Credit Jitender P. Dubey/U.S.D.A.

From New York Times: AUG. 28, 2014 – Parasites Practicing Mind Control

Carl Zimmer:

An unassuming single-celled organism called Toxoplasma gondii is one of the most successful parasites on Earth, infecting an estimated 11 percent of Americans and perhaps half of all people worldwide. It’s just as prevalent in many other species of mammals and birds. In a recent study in Ohio, scientists found the parasite in three-quarters of the white-tailed deer they studied.

One reason for Toxoplasma’s success is its ability to manipulate its hosts. The parasite can influence their behavior, so much so that hosts can put themselves at risk of death. Scientists first discovered this strange mind control in the 1990s, but it’s been hard to figure out how they manage it. Now a new study suggests that Toxoplasma can turn its host’s genes on and off — and it’s possible other parasites use this strategy, too.

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Toxoplasma manipulates its hosts to complete its life cycle. Although it can infect any mammal or bird, it can reproduce only inside of a cat. The parasites produce cysts that get passed out of the cat with its feces; once in the soil, the cysts infect new hosts.

Toxoplasma returns to cats via their prey. But a host like a rat has evolved to avoid cats as much as possible, taking evasive action from the very moment it smells feline odor.

Experiments on rats and mice have shown that Toxoplasma alters their response to cat smells. Many infected rodents lose their natural fear of the scent. Some even seem to be attracted to it.

Manipulating the behavior of a host is a fairly common strategy among parasites, but it’s hard to fathom how they manage it. A rat’s response to cat odor, for example, emerges from complex networks of neurons that detect an odor, figure out its source and decide on the right response in a given moment.

Within each of the neurons in those networks, thousands of genes are producing proteins and other molecules essential for relaying all of the necessary information throughout the body. Simple Toxoplasma seems ill-equipped to take over such a complicated system.

But a new study published in the journal Molecular Ecology hints that the parasite can do so by relying on an eerily elegant strategy. Think of the genes in a host as keys on a piano. Toxoplasma, it seems, simply plays some of the keys differently to produce a new melody.

A rat is made up of lots of different kinds of cells, from the neurons in its brain to the bone-producing cells in its skeleton to the insulin-making cells in its pancreas. Yet all of them carry the same 20,000 genes. Depending on the function of a particular cell, some of its genes are switched on and others are shut down.

Genes may be switched off, or silenced, by the attachment of molecular caps called methyl groups, a process called methylation. In order to switch a gene on again, the caps are removed.

Methylation does more than just allow cells to develop into a variety of organs. It lets them change the way they work in response to signals from the outside. In the brain, for example, neurons rely on this process to lay down long-term memories and change how an animal responds to its environment.

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Ajai Vyas, a neurobiologist at Nanyang Technological University in Singapore, wondered if Toxoplasma might wreak changes on rats by changing methylation in the rat brain — an idea “just hiding in plain sight,” he said.

In earlier research, Dr. Vyas and his colleagues had found that infected rats produced extra amounts of a neurotransmitter called arginine vasopressin. The neurotransmitter is manufactured by a small set of neurons buried in a structure of the brain called the medial amygdala.

Perhaps, Dr. Vyas thought, the parasite switched on the gene for arginine vasopressin in those cells. To find out, he and his colleagues ran a series of tests.

First they looked at the gene for arginine vasopressin in the medial amygdala of rats. In infected rats, they found, many of the molecular caps were missing, suggesting that Toxoplasma had “unsilenced” the gene in order to increase production of the neurotransmitter. The arginine vasopressin then might alter their response to cats.

If that were true, Dr. Vyas reasoned, then counteracting the parasite’s strategy should change the rat’s behavior.

He and his colleagues injected an extra supply of the molecular caps into infected rats. Some of the caps attached to the arginine vasopressin gene, and the rats became more fearful of the odor of cats.

That experiment led Dr. Vyas to see if he could make the rats behave as if they were being controlled by parasites — but without the parasites.

He and his colleagues removed molecular caps from the arginine vasopressin gene, mimicking what Toxoplasma might be doing to its hosts. The rats became reckless, feeling no fear at the whiff of cats.

“The animals looked like they were infected, even though there was no parasite around,” said Dr. Vyas.

“I think they could be on to something interesting,” said Michael Eisen, a biologist at the University of California, Berkeley, who has researched Toxoplasma in mice and was not involved in the new study. But he thought more experiments would have to be done to make a compelling case that the parasites really are using methylation to control their hosts.

Kami Kim of Albert Einstein College of Medicine, who also was not involved in the study, was more enthusiastic about the research. She also suggested that the strategy may be not be uncommon. In a review published this spring in the American Journal of Pathology, Dr. Kim and her colleagues survey a number of species that may use methylation to turn host genes on and off.

The bacteria that cause leprosy, for example, invade certain kinds of neurons and change some of their molecular caps. This methylation causes the neurons to change into stem cells much like those in an embryo. In this new state, the infected cells leave the nervous system and migrate through the body, spreading the bacteria with them.

“It looks like it will be a general strategy used by pathogens,” said Dr. Kim.