Finding the next pandemic threat early on

Even as public health officials are scrambling, with a decreasing likelihood of success, to prevent COVID-19 from becoming a pandemic, basic researchers are hunting for ways to identify future pandemic threats. Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) have developed a platform to rapidly test which coronaviruses were capable of infecting human cells. Beyond SARS, MERS and COVID-19, there are thousands of coronaviruses that infect more than a dozen animal species. To date, there has been no good method to determine which of those strains were capable of infecting humans. The NIAID team developed a platform that could rapidly screen strains, and showed that “several other lineage B coronaviruses are capable of entering human cells through an unknown receptor and that lineage B spike proteins can recombine to gain entry with a known host receptor. Taken together with the latest outbreak…, these findings underscore the importance of continued surveillance of coronaviruses at the sequence and functional levels in order to better prepare for the next emerging virus.” They reported their results in the Feb. 24, 2020, online issue of Nature Microbiology.

Microglial fresh start helps heal brain trauma

By killing off microglia, and then allowing them to repopulate, after traumatic brain injury, researchers at the University of Maryland School of Medicine and Trinity College Dublin were able to steer the cells to a less inflammatory phenotype in an animal model of traumatic brain injury (TBI). That, in turn, improved both the physical state of the brain and the behavioral abilities of the animals three months after injury. Microglia initially play an important role in removing cellular debris from the injury site. But their chronic activation leads to inflammation-mediated tissue destruction and, ultimately, impaired motor and/or cognitive function. In their experiments, the team killed off microglia by treating mice with the CSF-1R receptor inhibitor PLX-5622. After treatment was stopped, the microglia population rapidly bounced back, but with a less inflammatory phenotype. The delayed depletion improved brain anatomy and physiology as well as functional recovery. Treated animals showed less inflammation and less cell death three months after injury, and they performed better on cognitive and motor tests than untreated controls. Treatment was effective even when it was started four weeks after the original injury, demonstrating that there is an extended window of opportunity for giving recovery a helping hand after injury. The researchers reported their findings in the Feb. 25, 2020, issue of the Journal of Neuroscience.

Finding the silent majority

Scientists at Stanford University have developed a method to systematically identify silencer regions, expanding the understanding of functions of the noncoding genome. Noncoding regions make up 98% of the entire genome, and the more those regions are studied, the more functions are identified for what was once dismissed as being junk DNA. However, much as the coding genome receives a disproportionate amount of attention, regulatory regions that increase protein production have received disproportionate attention within the noncoding genome. In their work, the team developed a high-throughput screening method and used it to identify more than 5,000 candidate silencer elements for specific genes. In addition to characterizing their genomic locations and epigenetic signatures, they demonstrated that “deletion of silencers linked to drug transporter genes led to transcriptional upregulation of these genes and promoted chemotherapy resistance, suggesting that genetic variation in silencer regions may impact both biology and personalized medicine.” They reported their findings in the Feb. 24, 2020, online issue of Nature Genetics.

In a clinical study, 60% of patients with schizophrenia (subtype 1) had decreased gray matter volumes throughout the brain, which is the typical pattern. However, over a third of schizophrenia patients (subtype 2) had increased volumes of gray matter in the basal ganglia, but were otherwise similar to healthy controls. Credit: Penn Medicine

Anatomy study reveals schizophrenia subtypes

Researchers at the University of Pennsylvania have used structural MRI measurements in more than 300 schizophrenic individuals and more than 350 controls to identify two distinct subgroups of patients based on changes to grey matter, white matter and cerebrospinal fluid. Schizophrenia is a heterogenous disorder, and understanding its subtypes is likely to be a necessary prerequisite to improving treatment. Schizophrenia is thought to be accompanied by loss of neuronal grey matter throughout the brain, but in their study, the authors saw that pattern in only about 65% of patients. The others had a distinct pattern characterized by increased volume in certain midbrain structures, including the basal ganglia, and no loss of tissue elsewhere. In individuals with loss of grey matter, loss was greater with increasing duration of their illness, which, the authors wrote, “are more consistent with mechanisms associated with early neurodevelopmental disruption, inflammation, and cortical dysfunction” than the brain volume increases seen in other patients, which did not appear to be greater in patients with longer illness. The team published its results in the Feb. 26, 2020, online issue of Brain.

Increasing immune activity improves autoimmunity

Investigators at Washington University in St. Louis have suggested that innate immune function enhancement may be a – somewhat counterintuitive – treatment for atopic dermatitis (AD). As an autoimmune disease, AD is characterized by hyperactivity of some immune system components. However, the researchers showed that mouse models of atopic dermatitis had low levels of natural killer cells, innate immune cells associated with increased inflammation in the skin. They also showed that treatment with an interleukin-15 agonist that increased natural killer cell activity improved AD symptoms in the animals. “These findings reveal a previously unrecognized application of IL-15 superagonism, currently in development for cancer immunotherapy, as an immunotherapeutic strategy for AD,” the authors wrote. They published their findings in the Feb. 26, 2020, issue of Science Translational Medicine.

How cancer cells hibernate…

Researchers at the University of Padua and The Francis Crick Institute have demonstrated that the secreted frizzled-related protein 2 (SFRP2) played a key role in allowing breast cancer cells to colonize the lungs and remain there without forming overt metastases, a phenomenon known as indolence or dormancy. Breast cancer can stay indolent for decades after treatment before metastatic relapse, and a better understanding of the mechanisms underlying indolence might lead to therapeutic strategies to eradicate the cells responsible for such relapse. In their experiments, the authors demonstrated that the behavior of indolent breast cancer cells in the lung was governed by their interactions with lung alveolar epithelial cells. Interactions with alveolar type 1 cells set off SFRP2 expression and pro-survival signaling in breast cancer cells that entered the lung. “Our results indicate that carcinoma cells are highly responsive to signals coming from non-transformed epithelial cells at metastatic locations,” the authors wrote. “We propose that this will prove to be a recurring theme in the metastatic spread of epithelial cancers to distant epithelial tissues and, crucially, we demonstrate that interference in this crosstalk reduces survival of disseminated indolent breast cancer cells.” They reported their findings in the Feb. 24, 2020, issue of Nature Cell Biology.

…And who makes their bed

In separate work, investigators from the Johns Hopkins University School of Medicine have reported that myeloid-derived suppressor cells (MDSCs), a type of immune cell that represses antitumor immunity, were involved with preparing a “premetastatic niche” in the lung, and that a combination of two drugs could prevent them from doing so. Treating mice with the DNA methyltransferase inhibitor 5-azacytidine and the histone deacetylase inhibitor entinostat down-regulated the chemokine receptors CCL2 and CXCR2 on MDSCs, preventing their homing to the lung, as well as promoting fate-switching of the cells themselves. The authors concluded that “a combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.” Their results appeared in the Feb. 26, 2020, issue of Nature.

Blocking trash trashes MSI-hi tumors

Researchers at The University of Texas MD Anderson Cancer Center have shown that by blocking neddylation, a process analogous to ubiquitination, they were able to boost the effectiveness of checkpoint blockade in MSI-hi tumors. Such tumors have an extremely high mutation rate due to an underlying DNA repair defect, resulting in a high mutational burden. Checkpoint blocker Keytruda (pembrolizumab, Merck & Co. Inc.) is approved for any MSI-hi tumor regardless of anatomical origin, but the MSI-hi clinical response rate to Keytruda monotherapy is below 50%. In their work, the researchers showed that MSI-hi cells accumulated large numbers of misfolded protein aggregates, which they attempted to clear via neddylation. Blocking neddylation with Pevonedistat (MLN-4924) prevented those aggregates from being cleared, ultimately inducing immunogenic cell death. Pevonedistat and Keytruda were synergistic in animal models of MSI-hi tumors. They team concluded that “targeting proteome instability to enhance tumor immunogenicity may provide a promising treatment avenue, maximizing the number of patients who can achieve robust therapeutic responses to immunotherapy.” They reported their results in the Feb. 27, 2020, issue of Cancer Cell.

New splicing factor implicated in muscular dystrophy

Scientists at Southeast University in Nanjing, China, have discovered a role for the RNA-binding protein HNRNPA1 in a mouse model of myotonic dystrophy type 1 (DM1). A rare disorder that is caused by a nucleotide repeat expansion in the DMPK gene, DM1 can have widely varying symptoms. An underlying theme, though, seems to be that symptoms are “caused by a reversion to fetal RNA processing patterns in adult tissues due to the expression of toxic CUG RNA expansions,” the authors wrote. In their work, they showed that HNRNPA1, which had not previously been linked to DM1, also shifted splicing to a fetal-like pattern. “The demonstration that increased expression of HNRNPA1 recapitulates DM1 manifestations and splicing defects adds to a growing list of diseases attributed to HNRNPA1 misexpression and mutations, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis,” the authors wrote. Their work appeared in the Feb. 21, 2020, online issue of the Proceedings of the National Academy of Sciences.