Respiratory syncytial virus (RSV), while typically causing no more than a mild cold, is the leading cause of pneumonia in babies under the age of 1. It can also cause serious disease in the elderly. The virus is among those where repeat infections can be more severe due to the presence of antibody-dependent enhancement (ADE), where non-neutralizing antibodies bind to virus and help it enter and infect cells. Partly due to issues with ADE, which led to the recall of one vaccine in the 1960s, there is no licensed RSV vaccine to date despite numerous attempts. Researchers at Sanofi SA have developed a candidate antigen, consisting of multiple copies of the pre-Fusion protein conjugated to nanoparticles, and modified to mask epitopes that could lead to the production of non-neutralizing or poorly neutralizing antibodies that could pose a risk for ADE. The team reported that in both mice and nonhuman primates, their construct biased the immune response to neutralizing antibodies, “an attribute that facilitates the development of an effective RSV vaccine.” Their work appeared in the May 1, 2020, online issue of Science Immunology.
Insulin cuts both ways in vasculature
Hyperglycemia is bad for the vasculature, which is why diabetic individuals are at increased risk of cardiovascular disease. However, improved control of blood sugar levels have failed to improve cardiovascular outcomes in several large trials. Now, researchers at the University of Oxford have discovered the reason for this seeming paradox. They showed that insulin, though it indirectly benefited vasculature via its effects on blood sugar, it also led to reduced availability of the vasodilator nitric oxide. Treatment with an inhibitor of the metabolic enzyme dipeptidyl peptidase 4 (DPP4i) could reverse insulin’s effects on nitric oxide. “These findings may explain the inability of aggressive insulin treatment to improve cardiovascular outcomes, raising the question whether vascular insulin sensitization with DPP4i should precede initiation of insulin treatment and continue as part of a long-term combination therapy,” the authors wrote. They reported their results in the April 29, 2020, issue of Science Translational Medicine.
Transcriptomic insights into Parkinson’s disease
Researchers at the Karolinska Institute have used single cell transcriptomics to identify the cell types that are changed by risk variants for Parkinson’s disease (PD). Genomewide association studies (GWAS) have identified multiple genetic risk factors for both neurodevelopmental and neurodegenerative disorders in recent years. But which cell types are functionally affected by those risk variants remains unclear in many instances. The authors used single-cell transcriptomics in both mice and postmortem human brains and showed that unlike in neurodevelopmental disorders, where projection neurons are the main affected cell types, in PD there were changes in dopaminergic and other midbrain neurons, as well as in the enteric nervous system and oligodendrocytes. “Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression,” the authors wrote. “Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease.” They published their findings in the April 27, 2020, online issue of Nature Genetics.
Restoring synaptic transmission for rare neurodevelopmental disease
Researchers at the University of Wisconsin have unraveled the molecular mechanisms underlying the syt1-associated neurodevelopmental disorder. Missense mutations in synaptotagmin-1 (syt1) can cause the disorder, but its manifestations are heterogenous. The authors showed that mutations in syt1 impaired its ability to bind calcium and, consequently, impaired neurotransmitter release, which depends on the presence of calcium ions. They also showed that increasing calcium levels through treatment with the FDA-approved multiple sclerosis drug Ampyra (dalfampridine) could restore synaptic transmission. The authors concluded that their results “establish a molecular cause, basis for phenotypic heterogeneity, and potential treatment approach for syt1-associated neurodevelopmental disorder.” Their study appeared in the May 1, 2020, online issue of Neuron.
Polymerase k and drug resistance
Scientists at Memorial Sloan-Kettering Cancer Center have demonstrated that polymerase k, an enzyme involved in error-prone DNA repair, was retained in the nucleus in cancer cells, where it contributed to cancer drug resistance. However, its DNA repair function might not be the mechanism by which it fostered drug resistance. As they divide at warp speed, tumor cells tend to acquire more mutations, and those mutations in turn can lead to drug resistance. The authors showed that in melanoma cell lines, treatment with the targeted therapy vemurafenib led to a stress response that included increased polymerase K expression in the nucleus, but that overexpression of polymerase k did not increase the mutation rate of tumor cells. “It is possible that Polk overexpression is mutagenic in our studies (and that those mutations contribute to the observed drug resistance) but that our technologies were not sufficient to quantify this. However, it is important to note that we cannot exclude other nonmutagenic functions of Polk that could account for the increased drug resistance,” the authors wrote. They reported their findings in the April 28, 2020, issue of Science Signaling.
Where exercise-induced IL-6 comes and goes
Researchers at Columbia University have identified the origin of interleukin-6 (IL-6) released during exercise as muscle, and demonstrated that the cytokine’s benefits derive from its signaling to the bone. Exercise has a plethora of health benefits, and understanding the molecular underpinnings of those benefits could allow them to be replicated for people who can’t or don’t exercise. During exercise, blood levels of IL-6 increase sharply and high levels of IL-6 increase the capacity for vigorous exercise. The authors showed that this IL-6 was produced by muscle cells, and signaled in bone-building osteoblast cells, causing the release of osteocalcin, which in turn promoted nutrient uptake by muscle fibers. “This study provides evidence that a muscle-bone-muscle endocrine axis is necessary to increase muscle function during exercise in rodents and humans,” the authors wrote. “In the long run, these experiments may pave the way to harness osteocalcin signaling in muscle in order to improve muscle function” in patients with muscle loss. The team published its work in the April 27, 2020, online issue of the Journal of Clinical Investigation.
Sphingolipids accumulate in neurodegeneration
Researchers at the Harvard School of Public Health have identified the defective metabolism of sphingolipids, a class of lipids with many roles in cell metabolism, as a cause of neurodegeneration in a mouse model of motor neuron degeneration. Genomewide association studies (GWAS) have implicated retrograde membrane transport of materials taken up by cells via endocytosis in neurodegenerative disorders, but how problems with retrograde transport might cause neurodegeneration has remained unknown. In their experiments, the authors showed that in a mouse model of amyotrophic lateral sclerosis, animals with retrograde trafficking defects and motor neuron degeneration accumulated sphingolipids in their brains. “Preventing this buildup pharmacologically improved the symptoms of neurodegeneration and survival in these mice,” the authors wrote. “Thus, our data provide evidence that modulating sphingolipid metabolism will provide a therapeutic avenue to treat some forms of neurodegenerative disease.” Their work appeared in the April 28, 2020, online issue of the Proceedings of the National Academy of Sciences.
How does innate immunity remember? Not via polycomb
It was once thought that the innate immune system, whose responses to infections are faster but far less specific than those of the adaptive immune system, lacks immunological memory of previous pathogen encounters. Recent research, however, has provided some evidence to the contrary. The team looked at whether the polycomb complex, epigenetic proteins that help cells commit to lineage and develop a stable identity, might serve as a memory mechanism for pathogen exposures. However, the team showed that repeated exposure to lipopolysaccharide (LPS), a sign of bacterial exposure, did not affect polycomb marks in drosophila. The authors noted that there are other epigenetic mechanisms that might serve as mediators of immunological memory, or that “an epigenetic memory in the part of innate immunity, which involves the LPS-inducible genes analyzed in this study, is not required. The rapid gene induction system in the investigated cell system can be sufficient to maintain immunogenic responses strong enough to efficiently protect a host from an infection and thus make an epigenetic contribution unnecessary.” They reported their findings in the April 14, 2020, issue of PLoS ONE.
Antibiotics affect oxycodone effects
Researchers at the University of California at San Diego have found that antibiotics altered the microbiome and, as a result, the neuronal response to oxycodone, the painkiller whose overprescription has been at the center of the opioid epidemic. Opioids are frequently co-prescribed with antibiotics after surgery, and both alter the gut microbiome, which has emerged as an important modulator of behavior. The researchers found that when rats were given antibiotics and oxycodone simultaneously, compared to only oxycodone, they showed “widespread changes in the recruitment of neuronal ensembles that are activated by oxycodone intoxication and withdrawal, suggesting that the gut microbiome may play a role in opioid use and dependence,” the authors wrote. “Future studies are needed to better understand the molecular, neurobiological, and behavioral effects of microbiome depletion on addiction-like behaviors.” They published their results in the April 27, 2020, online issue of eNeuro.
Cabo as next annual shot?
Investigators at University of Nebraska Medical Center have developed a formulation of the HIV drug cabotegravir that led to yearlong therapeutic concentrations in mice and primates after a single injection. Cabotegravir administration has gone from daily to monthly, but in low-resource settings, even monthly administration can be a challenge. The authors developed a prodrug of cabotegravir by adding carbon chains, formulated it into nanocrystals, and embedded those in a biocompatible depot material. Specific versions “showed plasma [cabotegravir] levels above the protein-adjusted 90% inhibitory concentration for up to a year,” the authors wrote. “These prodrug modifications could substantially improve [cabotegravir] effectiveness.” They reported their results in the April 27, 2020, online issue of Nature Materials.