“…Nevertheless, several protocols of past curatives are being used for COVID-19 patients due to a lack of effective treatments or alternatives when extreme adverse drug events (ADE) are indicated. The innate immune system comprises inflammasomes ( Rasoulinejad et al, 2020 ), cytokines, and IFNs which help to clear viral disease and provide multi-system immunological protection ( Kopitar-Jerala, 2017 ; Rostamtabar et al, 2021 ). It has been shown that SARS-CoV2 is sensitive to type I IFN therapy in human cell lines ( Mantlo et al, 2020 ).…”
Section: Introductionmentioning
confidence: 99%
“… Fig. 1 Role of IFNs and other innate immunity elements in multi-system CoV disease Among innate elements, inflammasomes, ILs, and IFNs are of high importance ( Rasoulinejad et al, 2020 ). Innate immunity helps to prevent the spread of viruses and affects ACE2 − a major entry path for SARS-CoV2.…”
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), I
2
=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), I
2
=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.
“…Nevertheless, several protocols of past curatives are being used for COVID-19 patients due to a lack of effective treatments or alternatives when extreme adverse drug events (ADE) are indicated. The innate immune system comprises inflammasomes ( Rasoulinejad et al, 2020 ), cytokines, and IFNs which help to clear viral disease and provide multi-system immunological protection ( Kopitar-Jerala, 2017 ; Rostamtabar et al, 2021 ). It has been shown that SARS-CoV2 is sensitive to type I IFN therapy in human cell lines ( Mantlo et al, 2020 ).…”
Section: Introductionmentioning
confidence: 99%
“… Fig. 1 Role of IFNs and other innate immunity elements in multi-system CoV disease Among innate elements, inflammasomes, ILs, and IFNs are of high importance ( Rasoulinejad et al, 2020 ). Innate immunity helps to prevent the spread of viruses and affects ACE2 − a major entry path for SARS-CoV2.…”
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), I
2
=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), I
2
=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.
“…15 It is noteworthy that these mechanisms take effect in conjunction with other PRRs that are involved in the formation of the proinflammatory responses, such as inflammasomes-complexes of the innate immune system that are pivotal to the regulation of inflammation. 170,171 Future treatments should be designed to stop this futile induction cycle and overcome persistent injury to intact tissue.…”
Section: Role Of Tlrs In Normal Nervous System Functionmentioning
Neuropsychiatric disorders denote a broad range of illnesses involving neurology and psychiatry. These disorders include depressive disorders, anxiety, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, autism spectrum disorders, headaches, and epilepsy. In addition to their main neuropathology that lies in the central nervous system (CNS), lately, studies have highlighted the role of immunity and neuroinflammation in neuropsychiatric disorders. Toll‐like receptors (TLRs) are innate receptors that act as a bridge between the innate and adaptive immune systems via adaptor proteins (e.g., MYD88) and downstream elements; TLRs are classified into 13 families that are involved in normal function and illnesses of the CNS. TLRs expression affects the course of neuropsychiatric disorders, and is influenced during their pharmacotherapy; For example, the expression of multiple TLRs is normalized during the major depressive disorder pharmacotherapy. Here, the role of TLRs in neuroimmunology, treatment, and management of neuropsychiatric disorders is discussed. We recommend longitudinal studies to comparatively assess the cell‐type‐specific expression of TLRs during treatment, illness progression, and remission. Also, further research should explore molecular insights into TLRs regulation and related pathways.
“…By a MND in vivo model for expressing human SOD1‐G37R, a recent study showed immune protection of 2 vaccines, tgG‐DSE2lim and tgG‐DSE5b, against ALS based on the hypothesis that DSEs are formed following misfolding of SOD1 9 . TRAF6 contributes to the vicious cycle of neuroinflammation and inflammasome activation, cytokine production, and accumulation of SOD1 in the brain by exclusively interacting with the mutant form of SOD1 10–13 . Also, recent studies utilized intrabodies with proteolytic features targeted at mislocalized or accumulated types of intracellular TDP43 14…”
Section: Introductionmentioning
confidence: 99%
“…9 TRAF6 contributes to the vicious cycle of neuroinflammation and inflammasome activation, cytokine production, and accumulation of SOD1 in the brain by exclusively interacting with the mutant form of SOD1. [10][11][12][13] Also, recent studies utilized intrabodies with proteolytic features targeted at mislocalized or accumulated types of intracellular TDP43. 14 Role of TLRs as the linkage between the innate and adaptive immunity has been highlighted in ALS.…”
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.
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