Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Avian influenza A (H5N1) and severe acute respiratory syndrome (SARS) coronavirus are infections that cause a severe viral pneumonia leading to acute respiratory dysfunction syndrome and carry a high case-fatality rate. We have investigated innate immune responses to both viruses using primary human macrophages and respiratory epithelial cells as in vitro models. In contrast to human influenza A H1NI viruses, the H5N1 viruses hyper-induce cytokines (tumour necrosis factor [TNF]alpha, interferon beta) and chemokines (IP10, MIP1alpha, MCP) in in vitro cultures of primary human macrophages. A similar differential effect is observed in primary human bronchial epithelial cells and in type 2 pneumocytes although TNFalpha is not induced in respiratory epithelial cells. The cell signalling pathways responsible for this differential effect remain to be explored. Preliminary data suggest that such differential signalling involves p38 MAP kinase rather than NF-kappaB. SARS coronavirus infection of primary human macrophages is associated with a strong induction of chemokines without an associated type 1 interferon response. These observations may be relevant in disease pathogenesis.
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PMID:Pathogenesis of avian flu H5N1 and SARS. 1727 85

BACKGROUND. Given the apparent high mortality associated with the novel swine-origin influenza A/H1N1 virus (S-OIV) in Mexico, we aimed to study the cytokine profiles induced by S-OIV and the effect of immunomodulators. METHODS. We assayed cytokines and their messenger RNA (mRNA) levels in culture supernatants of human macrophages infected with H5N1, S-OIV California/04/2009 (S-OIV-CA), S-OIV Hong Kong/415742 (S-OIV-HK), or seasonal H1N1 with or without celecoxib and mesalazine. RESULTS. Among the 12 cytokines showing detectable levels, levels of 8 proinflammatory cytokines (interleukin [IL] 2R, IL-6, interferon [IFN] alpha, macrophage inflammatory protein [MIP] alpha, MIP-1beta, IFN-induced protein 10, regulated on activation, normal T cell expressed and secreted [RANTES], and monocyte chemotactic protein [MCP] 1) were higher in cells infected by H5N1 but similar among cells infected with H1N1, S-OIV-CA, or S-OIV-HK. The levels of the other 4 cytokines were similar for H5N1, H1N1, S-OIV-CA and S-OIV-HK. Among the 8 cytokines induced by H5N1, 6 were suppressed by celecoxib and mesalazine. The mRNA levels of tumor necrosis factor alpha, IFN-gamma, IL-6, and MCP-1 induced by H5N1 were higher than the levels of other cytokines at 12 and/or 24 h. CONCLUSIONS. No major cytokine storm, as seen in H5N1 infection, is associated with S-OIV infection of cell lines. The mainstay of treatment for uncomplicated S-OIV infections should be antiviral agents without immunomodulators. For individual S-OIV-infected patients with severe primary viral pneumonia, severe sepsis, and multiorgan failure, immunomodulators may be considered as an adjunctive therapy in clinical trials.
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PMID:Cytokine profiles induced by the novel swine-origin influenza A/H1N1 virus: implications for treatment strategies. 2003 May 55

Following the outbreak of novel severe acute respiratory syndrome (SARS)-coronavirus (CoV)2, the majority of nations are struggling with countermeasures to fight infection, prevent spread and improve patient survival. Considering that the pandemic is a recent event, no large clinical trials have been possible and since coronavirus specific drug are not yet available, there is no strong consensus on how to treat the coronavirus disease 2019 (COVID-19) associated viral pneumonia. Coronaviruses code for an important multifunctional enzyme named papain-like protease (PLP), that has many roles in pathogenesis. First, PLP is one of the two viral cysteine proteases, along with 3-chymotripsin-like protease, that is responsible for the production of the replicase proteins required for viral replication. Second, its intrinsic deubiquitinating and deISGylating activities serve to antagonize the host's immune response that would otherwise hinder infection. Both deubiquitinating and deISGylating functions involve the removal of the small regulatory polypeptides, ubiquitin and ISG15, respectively, from target proteins. Ubiquitin modifications can regulate the innate immune response by affecting regulatory proteins, either by altering their stability via the ubiquitin proteasome pathway or by directly regulating their activity. ISG15 is a ubiquitin-like modifier with pleiotropic effects, typically expressed during the host cell immune response. PLP inhibitors have been evaluated during past coronavirus epidemics, and have showed promising results as an antiviral therapy in vitro. In this review, we recapitulate the roles of PLPs in coronavirus infections, report a list of PLP inhibitors and suggest possible therapeutic strategies for COVID-19 treatment, using both clinical and preclinical drugs.
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PMID:Deubiquitinating Enzymes in Coronaviruses and Possible Therapeutic Opportunities for COVID-19. 3242 99