Measles vaccine far more protective than realized
Separate research teams have independently discovered the molecular mechanisms underlying the prolonged immune suppression following measles infection. The measles virus infects immune cells, but their numbers quickly rebound after acute infection. Nevertheless, infected individuals have an increased risk of infection and death that persists for years. In animal models, the authors demonstrated that acute measles virus infection wiped out memory B cells, so infected individuals lost immunity they had previously acquired to other diseases. Researchers at Harvard University, who published their results in the Nov. 1, 2019, issue of Science, concluded that "the WHO recently reported that between 2000 and 2017, [measles] vaccines have prevented more than 21 million deaths directly attributable to measles. These findings suggest that the number of deaths averted might be much greater, and they attest to the immense public health value of the measles vaccine." The second team, which hails from the Wellcome Sanger Institute and the University of Amsterdam, came to essentially the same conclusions, which they reported in the Nov. 1, 2019, issue of Science Immunology.
Tau spreads quickly but kills slowly
Researchers at Southampton University have used microfluidic cell culture modeling to demonstrate that misfolded tau spreads very rapidly, between healthy neurons, but it does not kill the cells in the short run. Tau pathology is a major feature of Alzheimer's disease (AD), as well as a group of neurodegenerative disorders collectively known as the tauopathies. In those disorders, misfolded tau both aggregates and spreads from cell to cell to seed disease. Neurons with tau tangles ultimately die, but how long it takes from infection to cell death has been unknown. The team developed a system to investigate the question, and showed that misfolded tau spread very rapidly between seemingly healthy neurons. However, "presence of misfolded tau is not directly cytotoxic to the neuron; the cells remain viable with limited deficits," the authors wrote. That suggests that neurons with tau pathology could be rescued with a therapeutic disease modifier and highlights an underappreciated time window for such therapeutic intervention. They reported their findings in the Oct. 28, 2019, issue of the Journal of Neuroscience.
PARP degradation joins trapping, inhibition
PARP inhibitors are among the most successful targeted therapies to reach cancer patients in recent years, but despite their name, they appear to work by trapping the PARP enzyme on DNA as much as by inhibiting its function. What is not clear, however, is how much each mechanism of action contributes to toxicity. Researchers at the University of Texas Southwestern Medical Center have developed a series of PARP degraders that work by tagging PARP for destruction by ubiquitin ligases. The approach, they wrote, "mimics PARP1 genetic depletion, which enables the pharmacological decoupling of PARP1 inhibition from PARP1 trapping.... by depleting PARP1, [the degrader] protects muscle cells and primary cardiomyocytes from DNA-damage-induced energy crisis and cell death. In summary, these compounds represent 'non-trapping' PARP1 degraders that block both the catalytic activity and scaffolding effects of PARP1, providing an ideal approach for the amelioration of the various pathological conditions caused by PARP1 hyperactivation." They reported their results in the Oct. 28, 2019, online issue of Nature Chemical Biology.
Drug-sensitive bacteria can be wolf in sheep's clothing
Investigators at the University of Leeds have demonstrated that between 3% and 10% of bacteria that respond to antibiotic treatment in standard tests have resistance genes that have been silenced by an additional mutation. Susceptibility testing is the mainstay of making antibiotic treatment decisions, but, as the authors wrote, "this approach relies on the assumption that such testing will reliably distinguish bacteria capable of expressing antibiotic resistance in a patient." In their work, they compared susceptibility testing and genome sequencing of nearly 1,500 strains of Staphylococcus aureus, and showed that 46 of those strains harbored antibiotic resistance genes that were not being expressed due to an additional mutation. The authors concluded that it is prevalent, transient and evades routine detection, "rendering it a significant potential threat to antibacterial chemotherapy," because silencing mutations can revert as bacteria proliferate in an infected patient. The researchers published their findings in the Oct. 29, 2019, online issue of mBio.
New inhibitor blocks, degrades MYC
Scientists at Northwestern University have identified an inhibitor of the transcription factor MYC with limited toxicity. MYC has long been considered undruggable, both because of its physical characteristics – as a transcription factor, it lacks the deep binding pockets that make up the most obvious docking sites for drugs – and because it is widely expressed in normal tissues. However, the authors were able to develop a compound, MYCi-975, with a reasonable therapeutic window. MYCi-975 inhibited MYC activity both by preventing dimerization with its binding partner MAX, and by increasing its degradation by the proteasome. Treatment with the inhibitor sensitized mice to checkpoint blockade, and the authors concluded that "one may envision a future treatment regimen in which an MYC inhibitor is given to patients for a limited period of time followed by immune checkpoint blockade, thus avoiding potential toxicities to normal tissues that may arise from prolonged MYC inhibition." Their work appeared in the Oct. 31, 2019, online issue of Cancer Cell.
Low-coverage genome sequencing gives answers in infertility
Researchers at Shandong University and the Chinese University of Hong Kong have gained new insights into the genomics of recurrent miscarriage. Roughly 1% to 2% of couples globally suffer from recurrent miscarriage, which remains a largely mysterious condition. The researchers tested whether low-pass genome sequencing would be able to find chromosomal abnormalities in infertile couples that had already had karyotyping performed. In a retrospective analysis of roughly 1,100 couples, the researchers detected chromosomal abnormalities in twice as many couples with low-pass genome sequencing as karyotype analysis had detected. The authors concluded that "low-pass GS identified underlying chromosomal aberrations in 1 in 9 RM-affected couples, enabling identification of a subgroup of patients with increased risk of subsequent miscarriage who would benefit from a personalized intervention," and in particular, pre-implantation genetic testing, should they attempt to become pregnant via in vitro fertilization. Their work appeared in the Oct. 31, 2019, issue of the American Journal of Human Genetics.
Study identifies metabolic path from stress to anxiety
Investigators at Zhejiang University and Southeast University have established xanthine as a link between stress and anxiety. Xanthine is a byproduct of nucleic acid metabolism. In their work, the authors showed that physical stress triggered changes in mitochondrial metabolism in CD4 "helper" T cells that resulted in nucleic acid breakdown and xanthine production and release. In the brain, xanthine affected oligodendrocytes via the adenosine A1 receptor. Mice lacking helper T cells were resistant to stress-induced anxiety. "Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior," the authors wrote. They published their findings in the Oct. 31, 2019, issue of Cell.
Gene therapy can treat, prevent heart failure
Scientists at the University of California at San Diego have demonstrated that gene transfer of the urocortin 2 gene could both treat and prevent heart failure with preserved ejection fraction (HFpEF) in mouse models. HFpEF, which makes up about half of all heart failure cases, is associated with diabetes, heart attacks and advanced age. Previous studies have shown that urocortin peptide was beneficial in animal models of heart failure, but because the peptide has an extremely short half-life, administering it is not a clinical option. The team showed that "Ucn2 gene transfer restores normal cardiac function in mice with age-related LV dysfunction and prevents development of LV dysfunction." They reported their results in the Oct. 31, 2019, online issue of Molecular Therapy.
iRhom2 is fibrosis friend, not foe
The protein iRhom2 is an essential partner in crime for ADAM17, a protease that cuts multiple targets, including the proinflammatory cytokine TNF-alpha and its receptors. Cutting by ADAM17 removes TNF receptors from the cell surface, and scientists at the University of Dusseldorf have demonstrated that this protects against liver fibrosis. Levels of ADAM17 and iRhom2 are elevated in fibrotic livers, but whether they fight fibrosis or contribute to it had been unclear. The scientists showed that in a mouse model of liver fibrosis, knockout animals lacking iRhom2 had increased fibrosis and accelerated disease progression compared to their wild-type cousins. Treating the knockouts with anti-TNF antibody Enbrel (etanercept) "reduced the presence of activated stellate cells and alleviated liver fibrosis," the authors wrote. Those data suggest that iRhom2-mediated inhibition of TNF receptor signaling protects against liver fibrosis. They presented their work in the Oct. 29, 2019, issue of Science Signaling.
Broad strategy for HIV bnAbs
Passively applied monoclonal broadly neutralizing antibodies (bnAbs) to HIV are showing promise in HIV treatment strategies, but developing a vaccine that elicits them in patients has so far been unsuccessful. Part of the reason is that antibodies need to undergo multiple rounds of selection from their naïve state to become broadly neutralizing. Researchers at the Scripps Research Institute, Harvard Medical School and the La Jolla Institute for Immunology have identified a strategy that could be successful in eliciting such antibodies. Broadly neutralizing antibodies have a long loop in a region of the antibody called heavy chain complementarity determining region 3 (HCDR3). Through deep sequencing, the researchers were able to identify precursors of broadly neutralizing antibodies in mice. The team then identified antigens that "primed responses from rare bnAb-precursor B cells in a mouse model, and in ex-vivo screens bound a range of potential bnAb-precursor human naive B cells. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs, and could be applied to most HCDR3-dominant antibodies from other pathogens," the authors wrote. Their work appeared in the Nov. 1, 2019, issue of Science.