Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists lift malaria’s cloak of invisibility

29.12.2005


The world’s deadliest malaria parasite, Plasmodium falciparum, sneaks past the human immune system with the help of a wardrobe of invisibility cloaks. If a person’s immune cells learn to recognize one of the parasite’s many camouflage proteins, the surviving invaders can swap disguises and slip away again to cause more damage. Malaria kills an estimated 2.7 million people annually worldwide, 75 percent of them children in Africa.



Howard Hughes Medical Institute (HHMI) international research scholars in Australia have determined how P. falciparum can turn on one cloaking gene and keep dozens of others silent until each is needed in turn. Their findings, published in the December 28, 2005, issue of Nature, reveal the mechanism of action of the genetic machinery thought to be the key to the parasite’s survival.

A DNA sequence near the start of a cloaking gene, known as the gene’s promoter, not only turns up production of its protein, but also keeps all other cloaking genes under wraps, according to Alan Cowman and Brendan Crabb, HHMI international research scholars at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, and their co-authors. "The promoter is all you need for activation and silencing," Cowman said. "It’s the main site of action where everything is happening."


Malaria parasites enter human blood from infected mosquitoes. The organisms invade and promptly remodel red blood cells. They decorate the surface of the cells they occupy with a protein called PfEMP1, made by the var gene family.

Using this versatile surface protein, the parasite evades the host’s immune system using two basic strategies. First, the protein sticks infected red blood cells to the blood vessel lining, removing the infected cells from circulation, where they would probably be destroyed.

But the protein cannot protect the parasite from patrolling immune cells, which eventually detect the invader and recruit troops to fight it. So, during a malaria infection, a small percentage of each generation of parasites switches to a different version of PfEMP1 that the body has never seen before. In its new disguise, P. falciparum can invade more red blood cells and cause another wave of fever, headaches, nausea, and chills.

"It’s like a leopard being able to change its spots," Cowman said. "New forms come up, and the immune system beats them down again. Because of this a lot of people think you need five years of constant exposure to malaria in its different disguises to gain immunity."

Many children do not survive malaria long enough to develop immunity. And without continuous exposure, hard-won immunity may disappear. For example, adults in Papua New Guinea who move to work in the mining industry, which is in mountainous regions that are mosquito-free, lose their immunity within a short time, he said.

The diverse genetic sequences of the 60 var cloaking genes all code for remarkably similar protein structures, the malaria researcher added. The genes are generally found at the ends of P. falciparum’s 14 chromosomes, although some of them cluster in internal regions.

In April 2005, Cowman, Crabb, and colleagues showed that var genes are regulated by the chromosome packaging, which unwraps one gene to be expressed at a time and literally packs away the inactive genes. In chromosomes, DNA can be encased so securely by some proteins that other proteins cannot access the nucleic acid for transcription, a process known as epigenetic silencing.

In their new paper, the researchers show that the activation of a var gene promoter is all it takes to trigger both the production that gene’s protein and the epigenetic silencing of the 59 other var genes. As in a previous study, they found that the physical location of the promoter within the nucleus seems to make a difference. The genetic activity occurred at the edge of the nucleus, with the activated promoter surrounded by chromosome ends containing silenced var genes.

To do this research, the scientists had to master the difficult technique of cloning large DNA sequences with a var promoter attached to various genes, inserting them into plasmid vectors, and introducing them into red blood cells infected by malaria parasites.

In one experiment, they set up a system where var gene expression could be studied using drug selection rather than the immune pressure that is normally needed to select variants in the field. Using this system they found that the information required for switching var genes on and off was contained within a promoter and that when active this could silence all of the var genes in the parasite.

"This is the first time anyone has actually been able to infiltrate an antigenic variation program," Cowman said. "We forced the cell to switch our gene on and others off." Their system can be used to study blood samples from people in the field to determine how they gain immunity over time.

Kirk Deitsch’s lab at Cornell University found that a piece of shared DNA--discarded in the process of translating the protein from its genetic instructions--was a key regulator of var gene silencing and activation. The HHMI researchers confirmed that this gene segment caused tighter packaging for the silenced genes, but they also showed that it wasn’t vital.

The researchers are continuing to disassemble the var gene machinery, piece by piece. They want to identify the proteins that unpack and activate the promoter region and learn more about the other proteins in the nuclear compartment that make it the prime spot for var gene activation. Eventually, they think their work may lead to new types of therapies that interfere with the parasite’s immune evasion strategies.

Cindy Fox Aisen | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Water world
20.11.2017 | Washington University in St. Louis

nachricht Carefully crafted light pulses control neuron activity
20.11.2017 | University of Illinois at Urbana-Champaign

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

Im Focus: Wrinkles give heat a jolt in pillared graphene

Rice University researchers test 3-D carbon nanostructures' thermal transport abilities

Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Antarctic landscape insights keep ice loss forecasts on the radar

20.11.2017 | Earth Sciences

Filling the gap: High-latitude volcanic eruptions also have global impact

20.11.2017 | Earth Sciences

Water world

20.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>