”The novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The escalating number of SARS-CoV-2-infected individuals has conferred the viral spread with the status of global pandemic. However, there are no prophylactic or therapeutic drugs available on the market to treat COVID-19, although several drugs have been approved. Recently, two articles using the comparative viral-human protein–protein interaction map revealed that the sigma-1 receptor in the endoplasmic reticulum plays an important role in SARS-CoV-2 replication in cells. Knockout and knockdown of SIGMAR1 (sigma-1 receptor, encoded by SIGMAR1) caused robust reductions in SARS-CoV-2 replication, which indicates that the sigma-1 receptor is a key therapeutic target for SARS-CoV-2 replication. Interestingly, a recent clinical trial demonstrated that treatment with the antidepressant fluvoxamine, which has a high affinity at the sigma-1 receptor, could prevent clinical deterioration in adult outpatients infected with SARS-CoV-2. In this review, we discuss the brief history of the sigma-1 receptor and its role in SARS-CoV-2 replication in cells. Here, we propose repurposing of traditional central nervous system (CNS) drugs that have a high affinity at the sigma-1 receptor (i.e., fluvoxamine, donepezil, ifenprodil) for the treatment of SARS-CoV-2-infected patients. Finally, we discussed the potential of other CNS candidates such as cutamesine and arketamine.”
Hashimoto, K. Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor. Eur Arch Psychiatry Clin Neurosci 271, 249–258 (2021). https://doi.org/10.1007/s00406-020-01231-x
Abstract: “The gut-brain axis is a bidirectional communication system which allows the central nervous system and gastrointestinal tract to interact with and respond to each other rapidly and effectively. It is becoming increasingly clear that major players in this complex system are gut bacteria. The mechanisms of signal transmission from bacteria to the brain are complex and not fully elucidated, but include neural, endocrine, immune, and metabolic pathways. It was initially demonstrated in a rodent model of depression that the gut microbiota was altered. This observation has been replicated in patients with major depression who show decreased microbial diversity. Furthermore, when rodents receive a microbiota transplant from a depressed patient their behaviour alters, as does their tryptophan metabolism and immune status. Several studies of psychobiotics (bacteria with a potential mental health benefit) have been conducted in healthy populations and in patients with depression. While some psychobiotics have shown efficacy in treating depression, other bacteria have yielded negative findings. Larger-scale, well-designed studies are required. EU-funded guidelines recommend that patients with depression or vulnerability to depression should be encouraged to enhance a plant-based diet with a high content of grains/fibres, fermented foods, and fish. A significant impact of such a diet is likely mediated through the gut microbiota.”
Dinan TG et al., Psychobiotics:Evolution of Novel Antidepressants. Mod. Trends Psychiatry 32: 134-143 (2021). doi: 10.1159/000510424.
Abstract: “Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring. The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs). Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring. In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene–environment interface during NDD pathogenesis. For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways. In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome. We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic ‘priming’ of offspring microglia and postnatal immune–brain crosstalk. The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms.”
Han, V.X., Patel, S., Jones, H.F. et al. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nature Reviews Neurol. 17: 564–579 (2021). https://doi.org/10.1038/s41582-021-00530-8
Abstract: “Cerebral collateral circulation and age are critical factors in determining outcome from acute ischemic stroke. Aging may lead to rarefaction of cerebral collaterals, and thereby accelerate ischemic injury by reducing penumbral blood flow. Dynamic changes in pial collaterals after onset of cerebral ischemia may vary with age but have not been extensively studied. Here, laser speckle contrast imaging (LSCI) and two-photon laser scanning microscopy (TPLSM) were combined to monitor cerebral pial collaterals between the anterior cerebral artery (ACA) and the middle cerebral artery (MCA) in young adult and aged male Sprague Dawley rats during distal middle cerebral artery occlusion (dMCAo). Histological analysis showed that aged rats had significantly greater volumes of ischemic damage than young rats. LSCI showed that cerebral collateral perfusion declined over time after stroke in aged and young rats, and that this decline was significantly greater in aged rats. TPLSM demonstrated that pial arterioles narrowed faster after dMCAo in aged rats compared to young adult rats. Notably, while arteriole vessel narrowing was comparable 4.5 h after ischemic onset in aged and young adult rats, red blood cell velocity was stable in young adults but declined over time in aged rats. Overall, red blood cell flux through pial arterioles was significantly reduced at all time-points after 90 min post-dMCAo in aged rats relative to young adult rats. Thus, collateral failure is more severe in aged rats with significantly impaired pial collateral dynamics (reduced diameter, red blood cell velocity, and red blood cell flux) relative to young adult rats.”
Abstract: “Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.”
Loske, J., Röhmel, J., Lukassen, S. et al. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children. Nat Biotechnol (2021). https://doi.org/10.1038/s41587-021-01037-9
Zhou X et al., Excess of COVID-19 cases and deaths due to fine particulate matter exposure during the 2020 wildfires in the United States
Science Advances 13 Aug 2021: Vol. 7, no. 33, eabi8789. DOI: 10.1126/sciadv.abi8789
Exposure to smoke, whether from air pollution or cigarette smoke, is believed to impair the function of white blood cells in the lungs, blunting the body’s immune response. The chemicals in particulate matter can also inflame cells lining the airways and lungs. In both cases, if the body is exposed to a virus in addition to air pollution, the immune response may be slowed and the person may develop a more severe illness than they would have otherwise, researchers say.
The findings build on the well-established connection between air pollution and respiratory-tract infections and conditions such as asthma. But the study is the first to show a statistical link between wildfire smoke and Covid-19 caseloads and deaths. …”