SIRPa blockade wakes up macrophages post-infection
Researchers at the University of Nantes and the University of Melbourne have discovered that the macrophage checkpoint SIRPa played an important role in reducing macrophage activity after inflammation, and that blocking SIRPa could restore their activity in cell culture, “which suggests a potential strategy to prevent hospital-acquired pneumonia,” according to the authors. Hospital-acquired pneumonia is the most frequent type of hospital-acquired infection. It has a 10% mortality rate, and is a major driver of broad-spectrum antibiotic use in intensive care settings, which in turn drives antibiotic resistance. Patients who are recovering from sepsis or trauma have a very high risk of developing pneumonia, and the authors hypothesized that this might be due to immunosuppression. They showed that macrophages from patients who had recovered from a critical illness functioned poorly for months afterward, due to epigenetic changes that induced high levels of tolerance. Mouse macrophages, too, were functionally impaired after dual infections, and that microenvironmental SIRPa signaling played a major role in that immune paralysis by reprogramming macrophage gene expression. “Our study prompts the development of therapies to treat hospital-acquired infections that are centered on restoration of host immunity rather than on avoidance of bacterial colonization, as is the case for most current strategies that seek primarily elimination of the pathogen” via antibiotics, the authors wrote. They published their findings in the May 18, 2020, issue of Nature Immunology.
Lasting immunity to SARS-CoV-2 looks possible
Researchers at the La Jolla Institute of Immunology have analyzed the T cells of convalescent patients after COVID-19 infection as well as healthy controls, and made two encouraging findings with respect to the T-cell response to SARS-CoV-2. First, the team showed that all patients had CD8-expressing “killer” T cells that recognized the SARS-CoV-2 spike protein, and 70% had CD4-expressing “helper” T cells that did the same. The team also “detected SARS-CoV-2-reactive CD4+ T cells in ~40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2.” Though it is not yet clear whether such pre-existing immunity leads to milder clinical cases, the finding is a hopeful sign that long-term immunity to coronaviruses is possible, which bodes well for the possibility of developing a long-acting vaccine. The team reported its results in the May 18, 2020, online issue of Cell.
Atherosclerosis, AD meet at the myelin
Researchers at Emory University have found shared protein expression patterns in the postmortem brains of patients with cerebral atherosclerosis or Alzheimer’s disease (AD). Atherosclerotic plaque is a risk factor for AD, prompting the authors to search for shared changes in the proteome of the two disorders. Using proteomic analysis of postmortem brains, they first separately identified protein changes in atherosclerosis and AD. Shared network analysis showed that individuals with both disorders had increased levels of oligodendrocyte proteins, and proteins related to remyelination processes and synapse formation and plasticity. “Together, these findings suggest [atherosclerosis] likely contributes to AD through its effects linked to reduction in synaptic signaling, regulation and plasticity, and increase in myelination, within the gray matter, which was the brain region examined,” the authors wrote. Their work appeared in the May 18, 2020, online issue of Nature Neuroscience.
T cell aging induces broad senescence
Investigators at the Spanish National Research Center have discovered that T cells with age-related metabolic dysfunction accelerated aging across the whole organism. Mitochondrial dysfunction is characteristic of multiple cell types in aging, and T cell aging has been linked to immune dysfunction, but not to age-related disease susceptibility as a whole. In their work, the authors knocked out the gene for the mitochondrial transcription factor A (Tfam) specifically in T cells, and showed that this resulted in cytokine accumulation and a broad inflammatory state that was similar to that seen with aging. “With the continuous extension of life expectancy, there is an urgent need to understand the common molecular pathways by which aging results in a progressively higher susceptibility to diseases,” the authors concluded. “Our results indicate that metabolic changes in the immune system promote age-related deterioration in other tissues, leading to multimorbidity and premature death. Their work appeared in the May 22, 2020, issue of Science.
P53 loss leads to immune evasion
Scientists at the Sanford Burnham Prebys Medical Discovery Institute have shown that delivery of tumor necrosis factor-alpha (TNFa) could reverse immune evasion of p53-mutated medulloblastoma cells. In animal models, treatment with TNFa synergized with checkpoint inhibitors and prolonged survival. Medulloblastoma is the most common pediatric brain tumor. Outlook differs between subtypes, but it is dismal for either newly diagnosed children with co-mutations in Shh and p53 and for recurrent patients with MYC amplification and p53 mutations. In their work, the team showed that loss of p53 prevented MHC1 molecules from reaching the cell surface and presenting antigens, rendering tumors invisible to the immune system. Treatment with low-dose TNFa restored antigen presentation by restoring expression of the peptide transporter Tap1 and the aminopeptidase Erap1. “These studies identified p53 as a key regulator of immune evasion and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy,” the authors wrote. Their work appeared in the May 18, 2020, online issue of Nature Neuroscience.
Early roots of ALS visible in teeth
Researchers at the Icahn School of Medicine at Mount Sinai have identified a signature of early life exposure to toxic metals that increased the risk of developing amyotrophic lateral sclerosis (ALS) in adulthood. ALS risk varies, even within families where people have the same underlying genetic mutations, which has set off a search for environmental risk factors. The team had previously demonstrated that metal exposure could be retrospectively determined by using the teeth, and linked metal exposure to the risk of neurodevelopmental disorders. Now, they used the technique to compare the childhood metal exposure of adult individuals with ALS and healthy controls. They identified “discrete developmental windows – postnatally to approximately 15 years – when metals, individually and in combination, are significantly associated with ALS onset decades later. We further verified the relevance of metal dysregulation in a transgenic mouse model of ALS. This is the first study to retrospectively link early life metal dyshomeostasis to ALS risk using tooth biomarkers,” the authors wrote. They concluded that “our study reveals direct evidence that altered metal uptake during specific early life time windows is associated with adult-onset ALS.” Their work appeared in the May 21, 2020, issue of the Annals of Clinical and Translational Neurology.
SLAPping down MDR gram-negatives
Microbiologists at the China Agricultural University’s College of Veterinary Medicine have developed new broad-spectrum, short linear antibacterial peptide (SLAP) antibiotic adjuvants, one of which, SLAP-S25, was effective against multidrug-resistant (MDR) gram-negative bacteria, including carbapenem- and colistin-resistant Escherichia coli, when combined with antibiotics. SLAP-S25 alone showed weak antibacterial activities against gram-positive and gram-negative bacteria. But broad synergies were seen between SLAP-S25 and other major classes of antibiotics against E. coli B2, including tetracycline, ofloxacin, rifampicin, cefepime and vancomycin. For example, the minimum inhibitory concentration of colistin decreased 32-fold in the presence of SLAP-S25, which also showed synergies with multiple antibiotics against antibiotic-sensitive E. coli isolates. SLAP-S25 was shown to damage bacterial membranes, allowing more antibiotics to accumulate in the bacteria. The team reported its findings in the May 18, 2020, online issue of Nature Microbiology.
ALK is candidate thinness gene
Investigators at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences and Nestle Research have identified a role for anaplastic lymphoma kinase (ALK) in keeping individuals thin in an obesogenic environment. ALK is well known for its role as a cancer driver when its translocation leads to ALK fusion proteins. But the natural function of ALK has not been well understood. Metabolic studies have largely looked for genes that confer an increased likelihood of being high weight, but there has been less research into genes that keep individuals thin in an environment that promotes weight gain. The team compared individuals whose body mass index (BMI) was in the lowest 5% of the population to those whose BMI was in the 30th to 50th percentile. They identified ALK as a candidate thinness gene and conducted animal studies to understand the molecular mechanism. “In Drosophila, RNAi mediated knockdown of ALK led to decreased triglyceride levels. In mice, genetic deletion of ALK resulted in thin animals with marked resistance to diet- and leptin-mutation-induced obesity,” they wrote. “Mechanistically, we found that ALK expression in hypothalamic neurons controls energy expenditure via sympathetic control of adipose tissue lipolysis.” The team published its work in the May 21, 2020, issue of Cell.
Can N-BPs become MVP again?
Scientists at Washington University in St. Louis have gained new insights into how nitrogen-containing bisphosphonates (N-BPs), which are used to prevent and treat osteoporosis and other bone disorders, including bone metastases, can cause bone necrosis and fractures instead. N-BPs like Fosamax (alendronate sodium, Merck & Co. Inc.) and its peers are still among the most widely prescribed drugs globally, but prescriptions have decreased by about half over the past decade due to their side effects, which are rare but, when they do occur, very serious. N-BPs act by inhibiting bone-destroying osteoclasts via affecting prenylation, a form of post-translational modification where the enzyme farnesyl diphosphate synthase (FDPS) adds lipids to proteins. The authors screened for genes that affected the function of N-BPs, and identified ATRAID as a gene whose absence conferred resistance to N-BP treatment in cell culture. In exome sequencing of patient samples, the team showed that osteonecrosis or fractures after N-BP treatment were associated with rare coding variants in the ATRAID gene. The authors concluded that their work “adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.” They published their findings in the May 20, 2020, issue of Science Translational Medicine.