The world according to GARP

A team from the Belgian Université catholique de Louvain has identified a novel method to block the actions of regulatory T cells, which inhibit other immune system cells. Regulatory T cells prevent autoimmunity but are also one of the stumbling blocks to developing effective cancer immunotherapies. One mechanism of action of regulatory T cells is the secretion of the cytokine TGF-beta1. In their studies, the authors showed that TGF-beta1 on the regulatory T cells' surface was bound to the protein GARP, and that the antibody ARGX-115 (Argenx BVBA) blocked their immunosuppressive actions. "These antibodies may serve as therapeutic tools to boost immune responses to infection or cancer via a mechanism of action distinct from that of currently available immunomodulatory antibodies," the authors concluded. "Used alone or in combination with tumor vaccines or antibodies targeting the CTLA4 or PD1/PD-L1 pathways, blocking anti-GARP antibodies may improve the efficiency of cancer immunotherapy." The work appeared in the April 22, 2015, issue of Science Translational Medicine.

Osteoporosis drug for asthma?

Scientists from the Mayo Clinic have reported that by blocking the calcium sensing receptor (CaSR), they were able to reduce the hypersensitivity of the airways that is a hallmark of allergic asthma. CaSR is better known for its role in bone, and there is a class of drugs that block that receptor, the calcilytics, that were originally developed as osteoporosis drugs. In their studies, the authors showed that CaSR also exists in the lungs and is activated by the polycations, a group of molecules that are found in high levels in asthmatics. Asthmatic patients and allergen-sensitized mice had higher levels of CaSR in airway smooth muscle than did healthy individuals. By ablating the calcium-sensing receptor, the researchers were able to prevent allergic stimuli from hypersensitizing mouse bronchi. The authors succinctly concluded that "calcilytics may represent effective asthma therapeutics." They published their findings in the April 22, 2015, issue of Science Translational Medicine.

PI3 kinase: Trouble everywhere

A team from the Cincinnati Children's Hospital Medical Center and Emory University has shown that PI3 kinase inhibition may be useful in individuals with Fragile X syndrome. Fragile X is the most frequent cause of inherited mental retardation, and autism-like behaviors are among its symptoms. Because hundreds of proteins are overexpressed in Fragile X syndrome, its molecular mechanisms have been hard to pin down. In their work, the authors showed that the PI3 kinase enhancer PIKE was one of those proteins, and that normalizing its levels normalized neuronal communication via the neurotransmitter glutamate in mouse and fly models of the disease. A second paper implicated a specific subunit of PI3 kinase in the results, and showed that decreasing expression of that subunit improved the cognitive abilities of Fragile X mouse models. The findings were published back to back in the April 23, 2015, issue of Cell Reports.

Protein transport linked to autoimmunity

A team from the Baylor College of Medicine has identified a mutation that led to deficits in the ER-Golgi system of protein transport, and severe autoimmune lung disease and arthritis. The team looked for autosomal dominant mutations that would affect autoimmunity because, they wrote, "monogenic disorders have proven powerful in elucidating biological mechanisms underlying autoimmunity, by showing that autoimmunity can arise from perturbations in several non-classical pathways." They identified five families with a syndrome of autoimmunity and lung disease apparently caused by an autosomal dominant mutation, and performed exome sequencing to identify genes that were mutated in affected individuals who developed autoimmunity at an average age of 3.5 years. They identified COPA as a candidate gene. Mechanistic studies showed COPA played a role in the protein trafficking of the Golgi and the endoplasmic reticulum. "It may seem unusual that mutation of a ubiquitously expressed protein in an essential trafficking pathway leads to an autoimmune syndrome restricted to the lung and joints. . . . We can only speculate that, in patients with COPA mutations, there are tissue-specific cells central to the disease that are sensitive to alterations in COPA function. . . . Future studies may elucidate how defects in COPA lead to ER stress and autoimmunity." Their work appeared in the April 20, 2015, online issue of Nature Genetics.

Depression has metabolic signature

Scientists from the Wellcome Trust Centre for Human Genetics at the University of Oxford have identified an unexpected genomic signature in major depression that implicates alterations in cell metabolism in the disease. The authors made their discoveries while sequencing nearly 6,000 women with recurrent major depression, many of whom had faced adverse life events such as childhood sexual abuse. Compared to nondepressed controls, the depressed subjects had higher levels of mitochondrial DNA, suggesting changes in metabolic state. They also had shorter telomeres, in line with earlier studies showing that stress leads to cellular aging. Both findings were associated with stress but "contingent upon entering a depressed state," the authors wrote. They added that "these findings identify increased amounts of mtDNA as a molecular marker of MD and have important implications for understanding how stress causes the disease." Their work appeared in the April 23, 2015, online issue of Current Biology.

TKM-Ebola works against current strain

Researchers from the University of Texas Medical Branch have shown that TKM-Ebola (Tekmira Pharmaceuticals Inc.) was able to cure primates infected with the Makona strain of Ebola virus that is responsible for the current outbreak in West Africa. The Makona strain has several genomic differences to strains behind previous outbreaks, including the Kikwit strain that is being used to test most therapies in development. In their work, the authors used viral Makona strain isolates to test TKM-Ebola both in vitro and in vivo. Three animals treated with the drug survived Ebola infection, while all three untreated controls died. More generally, TKM-Ebola consists of lipid nanoparticle-encapsulated short interfering RNAs (siRNAs) that could be more rapidly adapted to mutated versions if such adaptation becomes necessary. The work appeared in the March 23, 2015, issue of Nature.

Chikungunya vaccine

A team from the German Paul Ehrlich Institute has identified an antigen that could induce protective antibodies against Chikungunya virus. Chikungunya is among the viruses moving from tropical to formerly more temperate climes in the wake of climate change as well as globalization and, in this case, vector switch. Consequently, as with dengue fever, vaccines are becoming a higher priority in the developed world. E2 is a protein that helps Chikungunya fuse with the cells it infects, and in their work, the authors tested seven different epitopes derived from recombinant E2. They identified one such protein, which led to an antibody response in mice and partially protected them from infection. The authors concluded that the antigen they have identified is "a useful antigen for developing a vaccine when formulated with an appropriate adjuvant." They published their findings in the April 23, 2015, online issue of PLoS Neglected Tropical Diseases.

Clearing hepatitis B

Researchers from the Australian Walter and Eliza Hall Institute of Medical Research have shown that Smac mimetics, a class of drugs that promotes apoptosis by interfering with cellular inhibitors of apoptosis, might be useful for treating and possibly curing chronic hepatitis B virus (HBV) infection. Hepatitis B, like hepatitis C, often turns chronic and can cause cirrhosis and liver cancer when it does. In their experiments, the authors showed that one reason hepatitis B-infected cells survive is that a class of proteins known as cellular inhibitors of apoptosis prevented proinflammatory signaling from hepatitis B-infected cells and permitted infected cells to survive. Treatment with Smac mimetics, which antagonize the cellular inhibitors of apoptosis, allowed infected animals to clear infection. Based on the results, "antagonists of [cell inhibitors of apoptosis] may be efficacious in the treatment of chronic HBV infection and may promote elimination of virus." The findings were reported in two back-to-back papers in the April 20, 2015, online issue of the Proceedings of the National Academy of Sciences.

Use what you've got

Scientists from Duke University have developed a mathematical method to allow dosing of bacteria that produce extended spectrum beta-lactamase (ESBL) with beta-lactams. Beta-lactams are broad-spectrum antibiotics that are among the workhorses of clinical infection control, but resistance is an increasingly common problem when bacteria produce ESBL. In their work, the authors showed that some ESBL-producing bacteria could still be treated with beta-lactams, and developed mathematical procedures to find dosing regimens for successful treatments. The authors said that "ultimately, optimized dosing protocols could allow reintroduction of a repertoire of first-line antibiotics with improved treatment outcomes and preserve last-resort antibiotics." Their study appeared in PLOS Computational Biology on April 23, 2015.

How axons go kaput

Scientists at Washington University in St. Louis have identified the protein SARM1 as critical for initiating the destruction of axons after neuronal injury. Somewhat like apoptosis, or programmed cell death, axonal destruction is, in fact, self-destruction, a consequence of active cellular processes. In their experiments, the authors showed that SARM1 activity was required to induce axonal destruction after an injury. Once SARM1 was activated it triggered the rapid breakdown of the NAD+, which is a coenzyme that is important in many metabolic functions. "Our study provides further biological rationale for NAD+ augmentation as a therapeutic approach," the authors concluded. "Inhibition of SARM1-mediated NAD+ loss may be an alternative or synergistic therapeutic strategy for the treatment of neurologic disorders." They published their findings in the April 23, 2015, online issue of Science.

By Anette Breindl, Senior Science Editor