Monthly Archives: August 2013

Mouse study illustrates how foreign herpes DNA triggers immune response

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Herpes_vironFor the immune system to do its job in fighting off disease, it first has to be able to detect foreign intruders. Scientists have known for some time that when bacteria, viruses and other pathogens set off alarms in the immune system, this leads to the production of molecules such as interferon that rev up the body’s defenses. But until now, researchers lacked evidence from animal experiments to back up the theory of how the DNA from these pathogens first triggers this immune-activating cascade in the immediate, ‘innate’ immune response.

Previously, immunologist Zhijian “James” Chen, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues showed that when bacteria or viruses wile their way into host cells—either by tricking cell receptors to allow entry or getting engulfed by the cell membrane—their foreign DNA activates an enzyme called cyclicguanosine monophosphate–adenosine monophosphate synthase (cGAS). This enzyme then binds to the intruder’s DNA and triggers the next step in the cascade of immune events: the production of a second messenger, a small molecule called cyclicguanosine monophosphate–adenosine monophosphate (cGAMP).

In a mouse study published online today, Chen’s team demonstrates evidence of cGAS activity, in vivo, against infectious agents such as herpes virus, which uses DNA as its genetic material (unlike influenza or rotaviruses, which are examples of RNA-based pathogens).

The researchers exposed five mice that they had genetically engineered to lack cGAS to herpes simplex virus 1 (HSV1). All of those mice died from viral encephalitis, as did five control mice that also were exposed to the virus. Crucially, though, several of the mice engineered to lack cGAS died three days after exposure and had high titers of HSV1 in their brain tissue, whereas their control counterparts died beginning on the sixth day and had no detectable HSV1 in the brain. The cGAS-deficient rodents also had markedly lower levels of interferon—a key signaling molecule in of the immune system—indicating that mice without cGAS couldn’t mobilize an effective immune defense.

The role of cGAS show in the earlier in vitro study and this new rodent experiment has impressed other scientists. “This is a brand new antiviral mechanism that we didn’t know before,” says Luke O’Neill, a biochemist at Trinity College in Dublin, Ireland. “This research has really galvanized the field.”

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Discovery of gene variant lends muscle to understanding of statins’ side-effects

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Statin

The global market for statins has reached heart-stopping proportions, registering at almost $20 billion in 2012. In the US, one out of every four adults over the age of 45 is on statins, making these medications one of the leading types prescribed. The drugs work by lowering the liver’s production of low-density lipoproteins, also known as ‘bad’ cholesterol, which form the artery-clogging plaques that can lead to heart attack. But statins can cause significant side effects, ranging from sleeplessness to an increased risk of type 2 diabetes and potential liver damage.

One of the most common side effects is muscle pain and injury, which afflicts up to 38% of people taking statins. Now, researchers have hit upon a new gene variation that could explain why some individuals are less prone to this type of adverse reaction to such drugs.

The scientists themselves sound surprised at the discovery. “We weren’t focused on finding the cause of the muscle damage,” says Ronald Krauss, director of atherosclerosis research at Children’s Hospital Oakland Research Institute in California and lead author of the new study, which appears online today in Nature. “We were looking at cell lines from patients on statins to discover new gene variants and we found one that affects how the drug works.”

It’s not the first effort to look at statin side effect risks though the lens of genetics. Five years ago, researchers found that individuals on high doses of simvastatin—a statin marketed as Zocor by New Jersey-based Merck—who also carried a specific variant in the SLCO1B1 gene were fifteen times more likely to have muscle pain and injury, also known as myopathy. Based on these findings, which also correlated with markedly higher blood levels of a muscle damage biomarker, the US Food and Drug Administration set new guidelines recommending alternative medications for patients who need more than 40 milligram a day of simvastatin to lower their cholesterol.

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Intravenous vaccine for malaria offers robust protection in small clinical trial

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Almost half the world’s population lives in areas where malaria infection is a risk, yet no licensed vaccines exist to prevent this red blood cell parasite from causing almost half a million deaths each year. However, in a study published online today in Science, researchers report on a new vaccine that provided remarkable protection against Plasmodium falciparum, considered the deadliest of the four malaria strains.

“With this intravenous vaccine, we are striving to reach the World Health Organization goal of a [malaria] vaccine with 80 percent efficacy by 2025,” Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases (NIAID), in Bethesda, Maryland, told Nature Medicine. The clinical study was led by Robert Seder, an immunologist at the NIAID Vaccine Research Center, and involved a vaccine developed by Stephen Hoffman and his colleagues at Sanaria, a biotechnology company based in Rockville, Maryland.

Scientists have spent decades trying to block Plasmodium infections at different stages of the parasite’s life cycle—from the sporozoite that migrates out of the mosquito salivary gland and into host liver cells, to the merozoites that invade red blood cells before further developing into reproducing gametocytes.

To date, only one experimental vaccine, called RTS,S or Mosquirix, developed by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative, with funding from the Bill & Melinda Gates Foundation, has demonstrated a consistent protective effect. It is made with a combination of antigens from part of a sporozoite and a hepatitis B virus surface receptor. Early results suggested that three doses of the vaccine could cut the risk of infection among children aged 5 months to 17 months by half. But last year the results of a phase 3 clinical trial indicated that it offered only about 30–35% protection when given to infants between 6 weeks and 12 weeks of age.

Seder and his colleagues set their sights on developing a vaccine with at least 80% efficacy and also decided to focus on stopping malarial infections at the sporozoite stage—before the parasite ever gets into the red blood cells. The phase 1 clinical trial reported today included a total of 34 adults completing a series of intravenous vaccines at varying doses, with the most promising results at the highest dose levels. Six adults who received five vaccine injections at the highest dose all showed complete protection after they were subsequently infected deliberately with P. falciparum, while six of nine adults who received a series of four of the high-dose vaccines experienced similar protection following the immunization schedule.

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Compound kills drug-resistant tuberculosis through novel mechanism

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Tuberculosis is an old disease that demands new drugs. More than one million people die each year from Mycobacterium tuberculosis infections and a growing percentage of new infections—at least 9%—are caused by strains of the bacterium that can’t be killed with many of the drugs now available.

Q203

Q203

A new experimental compound could help. In a paper published online today in Nature Medicine, researchers describe a small molecule called Q203 that thwarts drug resistant tuberculosis infections in mice by targeting the mycobacterial cytochrome bc1 complex—a mechanism distinct from that of existing agents.

“Q203 works in ways [other] drugs do not,” says Kevin Pethe, project head of the antitubercular program at the Institute Pasteur Korea in Gyeonggi-do, who led the study, “and it can work against the resistant bacteria.”

To find the new drug, Pethe and his colleagues screened more than 100,000 different chemical compounds for their ability to inhibit tuberculosis growth in mouse macrophages. They identified 106 molecules that killed the infectious agent without harming the cells. One compound—a kind of imidazopyridine amide (IPA)—stood out for its ability to wipe out drug-resistant strains of tuberculosis isolated from human clinical specimens. The researchers made small changes in the chemical structure of this molecule to derive Q203. They then tested the compound in mice infected with tuberculosis, and observed that animals given Q203 showed fewer lung lesions than those treated with isoniazid, a commonly used first-line anti-tuberculosis agent. Plus, the mice tolerated high doses of Q203 without any noticeable side effects.

To understand how Q203 stopped the bacteria from replicating, Pethe’s team studied six tuberculosis strains that were resistant to the killing power of Q203. By sequencing the genome of these strains, the researchers pinpointed a common mutation affecting the cytochrome bc1 complex, which is involved in energy metabolism. They then measured ATP levels in Q203-sensitive cells and showed that ATP production dropped significantly after treatment with the experimental agent.

The finding that the cytochrome bc1 complex is the primary target of Q203 is consistent with the results of two recent reports showing that IPAs can broadly inhibit energy transduction systems in the tuberculosis pathogen. In one study, a British team from the University of Birmingham and the pharma giant GlaxoSmithKline discovered a series of molecules in this same chemical class directed at the same target, although these compounds were less effective at inhibiting tuberculosis growth as Q203. In the other report, Pethe and his former colleagues at the Novartis Institute for Tropical Diseases in Singapore showed that a panel of 13 different IPA compounds could kill tuberculosis by depleting ATP.

“The IPAs are getting a lot of attention because they are really inexpensive to make, seem to be safe, and work against drug-resistant tuberculosis,” says Marvin Miller, an organic chemist at the University of Notre Dame in South Bend, Indiana, who, together with colleagues at Indiana’s Eli Lilly, reported earlier this year on yet another set of IPAs with promising anti-tuberculosis and pharmacokinetic properties. “They could be very practical.”