Unpuzzling COVID-19:Tissue-related signaling pathways associated with SARS-CoV-2 infection and transmission

The highly infective coronavirus disease 19 (COVID-19) is caused by a novel strain of coronaviruses - the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - discovered in December 2019 in the city of Wuhan (Hubei Province, China). Remarkably, COVID-19 has rapidly spread across all continents and turned into a public health emergency, which was ultimately declared as a pandemic by the World Health Organization (WHO) in early 2020. SARS-CoV-2 presents similar aspects to other members of the coronavirus family, mainly regarding its genome, protein structure and intracellular mechanisms, that may translate into mild (or even asymptomatic) to severe infectious conditions. Although the mechanistic features underlying the COVID-19 progression have not been fully clarified, current evidence have suggested that SARS-CoV-2 may primarily behave as other β-coronavirus members. To better understand the development and transmission of COVID-19, unveiling the signaling pathways that may be impacted by SARS-CoV-2 infection, at the molecular and cellular levels, is of crucial importance. In this review, we present the main aspects related to the origin, classification, etiology and clinical impact of SARS-CoV-2. Specifically, here we describe the potential mechanisms of cellular interaction and signaling pathways, elicited by functional receptors, in major targeted tissues/organs from the respiratory, gastrointestinal (GI), cardiovascular, renal, and nervous systems. Furthermore, the potential involvement of these signaling pathways in evoking the onset and progression of COVID-19 symptoms in these organ systems are presently discussed. A brief description of future perspectives related to potential COVID-19 treatments is also highlighted

High dose of dexamethasone protects against EAE-induced motor deficits but impairs learning/memory in C57BL/6 mice

Multiple sclerosis (MS) is an autoimmune and neuroinflammatory disease characterized by demyelination of the Central Nervous System. Immune cells activation and release of pro-inflammatory cytokines play a crucial role in the disease modulation, decisively contributing to the neurodegeneration observed in MS and the experimental autoimmune encephalomyelitis (EAE), the widely used MS animal model. Synthetic glucocorticoids, commonly used to treat the MS attacks, have controversial effects on neuroinflammation and cognition. We sought to verify the influence of dexamethasone (DEX) on the EAE progression and on EAE-induced cognitive deficits. In myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced EAE female mice, treated once with DEX (50 mg/kg) or not, on the day of immunization, DEX decreased EAE-induced motor clinical scores, infiltrating cells in the spinal cord and delayed serum corticosterone peak. At the asymptomatic phase (8-day post-immunization), DEX did not protected from the EAE-induced memory consolidation deficits, which were accompanied by increased glucocorticoid receptor (GR) activity and decreased EGR-1 expression in the hippocampus. Blunting hippocampal GR genomic activation with DnGR vectors prevented DEX effects on EAE-induced memory impairment. These data suggest that, although DEX improves clinical signs, it decreases cognitive and memory capacity by diminishing neuronal activity and potentiating some aspects of neuroinflammation in EAE

Cholinergic neuroplasticity in asthma driven by TrkB signaling

Parasympathetic neurons in the airways control bronchomotor tone. Increased activity of cholinergic neurons are mediators of airway hyperresponsiveness (AHR) in asthma, however, mechanisms are not elucidated. We describe remodeling of the cholinergic neuronal network in asthmatic airways driven by brain-derived neurotrophic factor (BDNF) and Tropomyosin receptor kinase B (TrkB). Human bronchial biopsies were stained for cholinergic marker vesicular acetylcholine transporter (VAChT). Human lung gene expression and single nucleotide polymorphisms (SNP) in neuroplasticity-related genes were compared between asthma and healthy patients. Wild-type (WT) and mutated TrkB knock-in mice (Ntrk2tm1Ddg/J) with impaired BDNF signaling were chronically exposed to ovalbumin (OVA). Neuronal VAChT staining and airway narrowing in response to electrical field stimulation in precision cut lung slices (PCLS) were assessed. Increased cholinergic fibers in asthmatic airway biopsies was found, paralleled by increased TrkB gene expression in human lung tissue, and SNPs in the NTRK2 [TrkB] and BDNF genes linked to asthma. Chronic allergen exposure in mice resulted in increased density of cholinergic nerves, which was prevented by inhibiting TrkB. Increased nerve density resulted in AHR in vivo and in increased nerve-dependent airway reactivity in lung slices mediated via TrkB. These findings show cholinergic neuroplasticity in asthma driven by TrkB signaling and suggest that the BDNF-TrkB pathway may be a potential target

Stressing the airways: neuronal plasticity in allergic airway inflammation

Airway neurons carry multiple functions in the lungs, ranging from breathing regulation to sensing inhaled noxious particles. In asthma, it appears that these neurons function aberrantly due to being changed after a long period of inflammation, a process called neuroplasticity. Despite advancements in therapy, subsets of patients remain not well controlled. Understanding how neuroplasticity occurs in the asthmatic airways can yield novel druggable targets. Multiple factors can influence this process, such as circulating hormones, such as the ones found in psychological stress exposure, and immune cell-nerve interaction. Thus, we focused on the mechanisms governing neuroplasticity in asthma and associated modulators to understand better the disease pathophysiology and possible intervention opportunities. In human bronchial samples, we observed that asthma presented an increased area of cholinergic innervation. This branching and associated airway hyperresponsiveness were inhibited when a growth factor pathway called BDNF/TrkB signalling was inhibited in mice. Using a model of airway cholinergic neuron differentiation from stem cells, we have found that the glucocorticosteroid dexamethasone, a class of drugs widely prescribed for asthma and lung maturation, can induce changes in the functionality and differentiation of these neurons. In samples of patients with fatal asthma, we observed an increased innervation area surrounding the airways correlated to increased inflammatory cells surrounding nerve bundles. Finally, we have observed that chronic, but not acute, stress can potentiate inflammation in mice submitted to allergic lung inflammation and modulate neurotrophic factors’ expression in the lungs. Collectively, we have elucidated key mechanisms of neuroplasticity in asthma, paving the way for novel anti-asthma drugs

BDNF-TrkB signaling mediates cholinergic neuroplasticity in asthma

Background: Abnormal neuronal activity contributes to symptoms of allergic asthma, where increased cholinergic tone is observed. Neurotrophins such as brain-derived neurotrophic factor (BDNF) are target-derived neuronal growth factors and increasingly recognized as important in asthma. Here we hypothesized that there is an increased cholinergic neuronal density in asthmatic airways mediated by BDNF signaling via its receptor TrkB.Methods: Human bronchial biopsies were stained for the cholinergic marker vesicular acetylcholine transporter (VAChT). Human lung gene expression and single nucleotide polymorphisms (SNP) in neuroplasticity-related genes were compared between asthma and healthy patients. Wild-type (WT) and mutated TrkB knock-in mice (TrkBKI) with impaired BDNF signaling were chronically exposed to ovalbumin (OVA). Neuronal PGP9.5 and VAChT staining and airway narrowing in lung slices were assessed.Results: Compared to healthy subjects, bronchial biopsies from asthma patients showed a 1.6 fold higher VAChT+ area. Human lung transcriptome analysis revealed TrkB gene expression 1.5 fold higher in asthma versus healthy. Moreover, 5 SNPs in the BDNF gene and 1 SNP in the TrkB gene were associated with asthma. WT mice displayed a 2.0 fold increase in PGP9.5 and 1.8 fold increase in VAChT+ area, which were not observed in TrkBKI. Furthermore, airway hyperresponsiveness, as seen in WT mice, was not observed in TrkBKI.Conclusion: Our results indicate that in human asthma and in OVA exposed mice, an increased cholinergic nerve fiber density is present. The BDNF-TrkB signaling pathway might be involved in this neuroplasticity and genetic variation in both genes may contribute to asthma susceptibility