In silico design of a TLR4-mediating multiepitope chimeric vaccine against amyotrophic lateral sclerosis via advanced immunoinformatics.

Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disorder worldwide. In ALS, progressing disease can result from misfolding and aggregation of superoxide dismutase-1 (SOD1) or TAR DNA-binding protein 43 kDa (TDP43). An efficient immunotherapy for ALS should spare intact SOD1 while eliminating its dysfunctional variant. We utilized advanced immunoinformatics to suggest a potential vaccine candidate against ALS by proposing a model of dynamic TLR4 mediation and induction of a specific Th2-biased shift against mutant SOD1, TDP43, and TRAF6, a protein that specifically interacts with dysfunctional SOD1. SOD1, TDP43, and TRAF6 were retrieved in FASTA. Immune Epitopes Database and CTLpred suggested T/B-cell epitopes from disease-specific regions of selected antigens. A TLR4-mediating adjuvant, RS01, was used. Sequences were assembled via suitable linkers. Tertiary structure of the protein was calculated. Refined protein structure and physicochemical features of the 3D structure were verified in silico. Differential immune induction was assessed via C-ImmSim. GROningen MAchine for Chemical Simulation was used to assess evolution of the docked vaccine-TLR4 complex in blood. Our protein showed high structural quality and was nonallergenic and immune inducing. Also, the vaccine-TLR4 complex stability was verified by RMSD, RMSF, gyration, and visual analyses of the molecular dynamic trajectory. Contact residues in the vaccine-TLR4 complex showed favorable binding energies. Immune stimulation analyses of the proposed candidate demonstrated a sustained memory cell response and a strong adaptive immune reaction. We proposed a potential vaccine candidate against ALS and verified its physicochemical and immune inducing features. Future studies should assess this vaccine in animal studies.

Interferon therapy in patients with SARS, MERS, and COVID-19: A systematic review and meta-analysis of clinical studies.

Concern regarding coronavirus (CoV) outbreaks has stayed relevant to global health in the last decades. Emerging COVID-19 infection, caused by the novel SARS-CoV2, is now a pandemic, bringing a substantial burden to human health. Interferon (IFN), combined with other antivirals and various treatments, has been used to treat and prevent MERS-CoV, SARS-CoV, and SARS-CoV2 infections. We aimed to assess the clinical efficacy of IFN-based treatments and combinational therapy with antivirals, corticosteroids, traditional medicine, and other treatments. Major healthcare databases and grey literature were investigated. A three-stage screening was utilized, and included studies were checked against the protocol eligibility criteria. Risk of bias assessment and data extraction were performed, followed by narrative data synthesis. Fifty-five distinct studies of SARS-CoV2, MERS-CoV, and SARS-CoV were spotted. Our narrative synthesis showed a possible benefit in the use of IFN. A good quality cohort showed lower CRP levels in Arbidol (ARB) + IFN group vs. IFN only group. Another study reported a significantly shorter chest X-ray (CXR) resolution in IFN-Alfacon-1 + corticosteroid group compared with the corticosteroid only group in SARS-CoV patients. In a COVID-19 trial, total adverse drug events (ADEs) were much lower in the Favipiravir (FPV) + IFN-α group compared with the LPV/RTV arm (P = 0.001). Also, nausea in patients receiving FPV + IFN-α regimen was significantly lower (P = 0.03). Quantitative analysis of mortality did not show a conclusive effect for IFN/RBV treatment in six moderately heterogeneous MERS-CoV studies (log OR = -0.05, 95% CI: (-0.71,0.62), I2 = 44.71%). A meta-analysis of three COVID-19 studies did not show a conclusive nor meaningful relation between receiving IFN and COVID-19 severity (log OR = -0.44, 95% CI: (-1.13,0.25), I2 = 31.42%). A lack of high-quality cohorts and controlled trials was observed. Evidence suggests the potential efficacy of several combination IFN therapies such as lower ADEs, quicker resolution of CXR, or a decrease in inflammatory cytokines; Still, these options must possibly be further explored before being recommended in public guidelines. For all major CoVs, our results may indicate a lack of a definitive effect of IFN treatment on mortality. We recommend such therapeutics be administered with extreme caution until further investigation uncovers high-quality evidence in favor of IFN or combination therapy with IFN.

The involvement of the central nervous system in patients with COVID-19.

Coronaviruses disease (COVID-19) has caused major outbreaks. A novel variant, SARS-CoV-2, is responsible for COVID-19 pandemic. Clinical presentations and pathological mechanisms of COVID-19 are broad. The respiratory aspect of the disease has been extensively researched. Emerging studies point out the possibility of the central nervous system (CNS) involvement by COVID-19. Here, we discuss the current evidence for CNS involvement in COVID-19 and highlight that the high pathogenicity of SARS-CoV-2 might be due to its neuroinvasive potential.