A team of scientists from A*STARs Institute of Molecular and Cell Biology (IMCB) has discovered the secret recipe for antidotes that could neutralize the deadly plant toxin ricin, widely feared for its bioterrorism potential, as well as the Pseudomonas exotoxin (PE) responsible for the tens of thousands of hospital-acquired infections in immune-compromised patients all over the world. The results of this first ever genome-wide study to understand how the ricin and PE toxins attack cells may also be useful for designing more effective antidotes against diphtheria and shiga-like toxins secreted by infectious strains of E. coli bacteria, such as those responsible for the recent food poisoning outbreak in Germany.
In this study, the team led by IMCB Principal Investigator, Dr. Frédéric Bard examined the entire human genome of about 22,000 genes to identify those genes of normal host cell processes which Ricin and PE toxins hijack in order to kill the cell. Of the several host genes identified, the team discovered one called ERGIC2 to be an attractive therapeutic target because it is not only highly essential for Ricin but also required for PE intoxication. "This means that we could potentially develop a generic antidote that is effective against the two different types of toxins by blocking ERGIC2 function," says Bard.
Ricin is an extremely potent poison that can easily be purified from the widely available castor beans. Security experts say an amount roughly equivalent to half a grain of rice is enough to kill an adult, making it 1,000 times more poisonous than cyanide. There are currently no known antidotes for ricin, and the ease of production of this tasteless, odorless plant toxin is why ricin is feared for its immense bioterrorism potential.
Healthcare-acquired infections (HAIs) are a major healthcare problem affecting millions of people around the world. The Centers for Disease Control and Prevention (CDC) estimates that HAIs leads to $45 billion in healthcare costs annually and results in nearly 100,000 deaths per year, making HAIs the fourth leading cause of death. The bacteria Pseudomonas aeruginosa that secretes PE toxin is a common cause of HAIs in vulnerable individuals, including those with burn injuries or receiving intensive care. Unfortunately, HAIs are increasingly difficult to treat because the emergence of antibiotic-resistant bacteria is on the rise. Similarly, the E. coli strain that produces stoxins, found in the recent deadly food poisoning cases in Germany, were also resistant to antibiotics. Moreover, in food poisoning cases caused by such toxin-producing bacteria, doctors refrain from using antibiotics as killing the bacteria actually causes more toxins to be released, bringing on the worst symptoms of the illness. There is therefore a real need worldwide for antidotes against these life-endangering toxins.
Highlighting the significance of this study, Bard adds, "Through this genome-wide screen, our understanding of how toxins interact with human cells at the molecular level expanded tremendously. Our hope is that with these new therapeutic targets identified from the human genome, we will be one step closer to finding toxin antidotes that will make hospital-acquired infections and enterotoxic E. coli outbreaks a thing of the past."
Though immunologically different from each other, ricin, PE, diphtheria and shiga toxins all kill by destroying the cells protein synthesis factories, the place where all proteins necessary for the cells survival are produced. To travel to these protein factories in the cell, the toxins first trick the host cell into turning off a natural defense mechanism that destroys foreign proteins. Next, they exploit the host cells internal transport pathway to reach the protein factories, destroying them and killing the cell. When this happens, cell death is imminent. If not contained, toxins released from dead cells can spread to neighboring healthy cells, resulting in rapid and widespread tissue and organ damage.
By identifying the specific host genes required for these toxins to attack the cells protein factories, this study effectively singled out the attractive therapeutic targets from the entire human genome for developing antidotes that could potentially be effective against any toxins that share the same mode of action. For instance, ERGIC2 was found to be an important component of the cells internal transport pathway that the toxins hijack to reach the cells protein factories.
The research can be found in the July 21, 2011 advance online issue of Developmental Cell. The citation is: Genome-wide RNAi screens identify genes required for Ricin and PE intoxications by Dimitri Moreau, Pankaj Kumar, Shyi Chyi Wang, Alexandre Chaumet, Shin Yi Chew, Hélène Chevalley and Frédéric Bard.