Obsah obrázku květina, rostlina Popis byl vytvořen automaticky SARS-CoV-2 pathophysiology 1.Renin-angiotensin-aldosteron systém (RAS) •Receptor ACE2 •Pathologic regualation of RAS and covid 19 2. 2. • Blood pressure icon Royalty Free Vector Image - VectorStock 1.Renin-angiotensin-aldosteron systém (RAS) •Receptor ACE2 •Pathologic regualation of RAS and covid 19 2. 2. 2.Non-specific (innate) immunity a mutagenesis •Mechanisms of innate immunity •Mutations raised by host cell 3. 3. 3. • Free Mutation Coronavirus Icon of Line style - Available in SVG, PNG, EPS, AI & Icon fonts Blood pressure icon Royalty Free Vector Image - VectorStock 1.Renin-angiotensin-aldosteron systém (RAS) •Receptor ACE2 •Pathologic regualation of RAS and covid 19 2. 2. 2.Non-specific (innate) immunity a mutagenesis •Mechanisms of innate immunity •Mutations raised by host cell 3. 3. 3. 3.Specific immune reaction and complement activation •Antibody response •Inflamation 4. Free Mutation Coronavirus Icon of Line style - Available in SVG, PNG, EPS, AI & Icon fonts Blood pressure icon Royalty Free Vector Image - VectorStock Antibodies - Free education icons 1.Renin-angiotensin-aldosteron systém (RAS) •Receptor ACE2 •Pathologic regualation of RAS and covid 19 2. 2. 2.Non-specific (innate) immunity a mutagenesis •Mechanisms of innate immunity •Mutations raised by host cell 3. 3. 3. 3.Specific immune reaction and complement activation •Antibody response •Inflamation 4. 4. 4.Mechanisms of endothelial injury •Cytokine storm, ARDS • Free Mutation Coronavirus Icon of Line style - Available in SVG, PNG, EPS, AI & Icon fonts Blood pressure icon Royalty Free Vector Image - VectorStock Antibodies - Free education icons Diagnostics | Free Full-Text | Molecular and Serological Tests for COVID-19. A Comparative Review of SARS-CoV-2 Coronavirus Laboratory and Point-of-Care Diagnostics | HTML S-protein structure Molecules in pathogenesis: angiotensin converting enzyme 2 (ACE2) | Journal of Clinical Pathology S-protein structure and interaction wih ACE2 Vývojový diagram: zpoždění: Ang I Ang I > Angiotensinogen Renin The role of RAS in SARS-Cov-2 infection Angiotensin I 10-amino-acids > AT1R > Ang I Angiotensin II 8-amino-acids Angiotensin I 10-amino-acids Angiotensin-converting enzyme 1 Angiotensinogen Renin Angiotensin II receptor type 1 •Increased permeability •Vasoconstriction •Endothelial disfunction •Lung edema, •Thrombocyte activation •Coagulation •Inflamation •Mesenchymal proliferation The role of RAS in SARS-Cov-2 infection > AT1R > Ang I Angiotensin II 8-amino-acids Angiotensin I 10-amino-acids Angiotensin-converting enzyme 1 Angiotensinogen Renin Angiotensin II receptor type 1 > AT2R Angiotensin II receptor type 2 •Increased permeability •Vasoconstriction •Endothelial disfunction •Lung edema, •Thrombocyte activation •Coagulation •Inflamation •Mesenchymal proliferation The role of RAS in SARS-Cov-2 infection > AT1R Ang I Angiotensin II 8-amino-acids Angiotensin I 10-amino-acids Angiotensin-converting enzyme 1 > Angiotensinogen Renin Angiotensin II receptor type 1 angiotensin 1-7 > AT2R Angiotensin II receptor type 2 Angiotensin-converting enzyme 2 •Increased permeability •Vasoconstriction •Endothelial disfunction •Lung edema, •Thrombocyte activation •Coagulation •Inflamation •Mesenchymal proliferation The role of RAS in SARS-Cov-2 infection > MAS-R > AT1R Covid-19 with solid fill Ang I Angiotensin II 8-amino-acids Angiotensin I 10-amino-acids Angiotensin-converting enzyme 1 > Angiotensinogen Renin Angiotensin II receptor type 1 angiotensin 1-7 > AT2R Angiotensin II receptor type 2 Angiotensin-converting enzyme 2 > MrgD Alamandine = Decarboxylated Ang 1-7 Mas-receptor MrgD- Mas-related G protein-coupled receptor D •Increased permeability •Vasoconstriction •Endothelial disfunction •Lung edema, •Thrombocyte activation •Coagulation •Inflamation •Mesenchymal proliferation The role of RAS in SARS-Cov-2 infection > MAS-R > AT1R Covid-19 with solid fill Ang I Angiotensin II 8-amino-acids Angiotensin I 10-amino-acids Angiotensin-converting enzyme 1 > Angiotensinogen Renin Angiotensin II receptor type 1 angiotensin 1-7 > AT2R Angiotensin II receptor type 2 Angiotensin-converting enzyme 2 > MrgD Alamandine = Decarboxylated Ang 1-7 Mas-receptor MrgD- Mas-related G protein-coupled receptor D •Increased permeability •Vasoconstriction •Endothelial disfunction •Lung edema, •Thrombocyte activation •Coagulation •Inflamation •Mesenchymal proliferation •NO production •Vasodilatation •Endothelia protection •Anti oxidative stress •Anti-fibrosis The role of RAS in SARS-Cov-2 infection MAS-R AT1R Covid-19 with solid fill Ang I Angiotensin II 8-amino-acids Angiotensin I 10-amino-acids Angiotensin-converting enzyme 1 Angiotensinogen Renin Angiotensin II receptor type 1 angiotensin 1-7 AT2R Angiotensin II receptor type 2 Angiotensin-converting enzyme 2 MrgD Alamandine = Decarboxylated Ang 1-7 Mas-receptor MrgD- Mas-related G protein-coupled receptor D •Increased permeability •Vasoconstriction •Endothelial disfunction •Lung edema, •Thrombocyte activation •Coagulation •Inflamation •Mesenchymal proliferation •NO production •Vasodilatation •Endothelia protection •Anti oxidative stress •Anti-fibrosis Bradyk BK1R BK2R HMWK Kalikrein •Vasidilation, NO •Inflamation •Cytokine •Endothelial dysfunction • The role of RAS in SARS-Cov-2 infection BK is hydrolyzed by ACE into des-Arg9 BK and inactive products. ACE2 breaks down des-Arg9-BK into inactive peptides. BK and des-Arg9-BK interact with two bradykinin receptors (BK1R and BK2R) > MAS-R > AT1R Covid-19 with solid fill Ang I Angiotensin II 8-amino-acids Angiotensin I 10-amino-acids Angiotensin-converting enzyme 1 > Angiotensinogen Renin Angiotensin II receptor type 1 angiotensin 1-7 > AT2R Angiotensin II receptor type 2 Angiotensin-converting enzyme 2 > MrgD Alamandine = Decarboxylated Ang 1-7 Mas-receptor MrgD- Mas-related G protein-coupled receptor D •Increased permeability •Vasoconstriction •Endothelial disfunction •Lung edema, •Thrombocyte activation •Coagulation •Inflamation •Mesenchymal proliferation •NO production •Vasodilatation •Endothelia protection •Anti oxidative stress •Anti-fibrosis The role of RAS in SARS-Cov-2 infection ACE inhibitors: •Captopril •Enalapril •Fosinopril •Lisinopril AT1R inhibitors: •Valsartan •Telmisartan •Losartan •Olmesartan Mechanisms of innate immunity (fast but non-specific response) Detection of pathogenic microorganisms •Membrane receptors •Intracellular receptors of foreign nucleic acids •Cytokine signalling Intracellular signalling pathways Activation of transcription / gene expression •Expression of cytokines •Activation of specific immune response •Elimination of microorganisms •Use of gene • • DNA damage repair Mechanisms of innate immunity Toll-like receptors (TLRs) TLR Vyhrazeno: TLR TLR DNA with solid fill DNA with solid fill DNA with solid fill DNA with solid fill DNA with solid fill NF-κB Activated by extracellular signals from pathogens: Polysacharides, RNA, DNA, proteins, lipopeptides, endotoxins,.. IRFs IFN IFNAR gamma-activated sequences, IFN-stimulated response elements DNA with solid fill GAS ISRE STAT Covid-19 with solid fill Cyclic GMP-AMP synthase Cytoplasmic sensor of DNA Cyclic guanosine monophosphate–adenosine monophosphate - Wikipedia Cyclic guanosine monophosphate–adenosine monophosphate cGAS DNA with solid fill Covid-19 with solid fill ATP+GTP ER Stimulator of interferon genes STING cGAMP Interferone receptors IRGs – interferone regulated genes Cytokines Host-directed editing enzymes: APOBEC, ADAR, AID.. APOBEC family members APOBEC1 APOBEC2 APOBEC3A APOBEC3B APOBEC3C APOBEC3D APOBEC3F APOBEC3G APOBEC3H APOBEC4 AID (activation induced deaminase) •APOBEC ("apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like") is a family of evolutionarily conserved cytidine deaminases. •Discovered due to their ability to eliminate HIV infection •When misregulated, are a major source of mutation in numerous cancer types. •AID is a part of adaptive immunity; it is responsible for hypermutation of variable immunoglobulin regions in lymphocytes Interaction of hepatitis C virus with the type I interferon system ADAR1 active site Mechanism of action: Deamination of adenosine to inosine Destabilize RNA Mismatch pairing when replicated ADAR - adenosine deaminase acting on RNA responsible for binding to double stranded RNA (dsRNA) and converting adenosine (A) to inosine (I) by deamination. ADAR protein is a RNA-binding protein, which functions in RNA-editing through post-transcriptional modification of mRNA transcripts by changing the nucleotide content of the RNA Dysregulation associated with: Aicardi–Goutières syndrome and Bilateral Striatal Necrosis/Dystonia, cancer (HCC) The results suggest that the heterogeneous mutation patterns are mainly reflections of host (i) antiviral mechanisms that are achieved through APOBEC, ADAR, and ZAP proteins, and (ii) probable adaptation against reactive oxygen species. Signatures of Mutational Processes in Human Cancer Signature 2 has been attributed to activity of the AID/APOBEC family of cytidine deaminases. Study: Identification of novel bat coronaviruses sheds light on the evolutionary origins of SARS-CoV-2 and related viruses. Image Credit: Binturong-tonoscarpe / Shutterstock Loss of genes in NF-κB signalling pathway Expansion of the APOBEC3 gene locus Cureus | Coronavirus (COVID-19) Fulminant Myopericarditis and Acute Respiratory Distress Syndrome (ARDS) in a Middle-Aged Male Patient Covid-19 with solid fill viral mRNA Mechanisms of endothelial damage by SARS-CoV2 viral mRNA > MAS-R Covid-19 with solid fill > ATR1 Ang I S-protein Mechanisms of endothelial damage by SARS-CoV2 viral mRNA MAS-R Covid-19 with solid fill ATR1 Covid-19 with solid fill Ang I Insuficient production of angiotensin 1-7 Inhibition of ACE2 protease S-protein Mechanisms of endothelial damage by SARS-CoV2 Activation of Angiotensin II receptor 1 viral mRNA MAS-R Covid-19 with solid fill ATR1 Covid-19 with solid fill Ang I •Increased permeability •Vasoconstriction •Endothelial disfunction •Thrombocyte activation •Coagulation •Inflamation •Mesenchymal proliferation •NO production •Vasodilatation •Endothelia protection •Anti oxidative stress •Anti-fibrosis Insuficient production of angiotensin 1-7 Inhibition of ACE2 protease Activation of Angiotensin II receptor 1 S-protein Mechanisms of endothelial damage by SARS-CoV2 Lung edema ARDS Mechanisms of endothelial damage by SARS-CoV2 viral mRNA Covid-19 with solid fill viral mRNA IgM S-protein Mechanisms of endothelial damage by SARS-CoV2 viral mRNA Covid-19 with solid fill viral mRNA C6 C7 C8 C9 IgM S-protein C3b C5b Skull with solid fill C1 complex C4b Vývojový diagram: zpoždění: C2b C2b C5a Activation of complement by IGM (classical pathway) C3a C3a Mechanisms of endothelial damage by SARS-CoV2 viral mRNA Covid-19 with solid fill viral mRNA C6 C7 C8 C9 IgM S-protein C3b C5b Skull with solid fill C1 complex C4b Vývojový diagram: zpoždění: C2b C2b C5a Activation of complement by IGM (classical pathway) C3a C3a IgG Mechanisms of endothelial damage by SARS-CoV2 viral mRNA Covid-19 with solid fill viral mRNA C6 C7 C8 C9 IgM S-protein C3b C5b Skull with solid fill C1 complex C4b Vývojový diagram: zpoždění: C2b C2b C3a C5a Opsonization Activation of complement receptors Activation of complement by IGM (classical pathway) Cytokines: TNF, IL-1, IL-6, IL-8, and IL-12 Cytokine storm Mechanisms of endothelial damage by SARS-CoV2 viral mRNA Covid-19 with solid fill viral mRNA C6 C7 C8 C9 IgM IgG S-protein C5AR1 (CD88) C5AR2 (GRP77) H2O2 O. C3b C5b Skull with solid fill C1 complex C4b Vývojový diagram: zpoždění: C2b C2b C3a C5a Myeloperoxidase Reactive oxygen Opsonization Activation of complement receptors Activation of complement by IGM (classical pathway) Neutrophil Cytokines: TNF, IL-1, IL-6, IL-8, and IL-12 Cytokine storm C3b C5b C5a C5 Eculizumab is humanized therapeutical antibody that binds C5 complement and prevents its cleavage by C3b. It is used to treat paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and neuromyelitis optica. Eculizumab Fig. 1 Fig. 1 High viral load Delayed immune response: •Primoinfection •Exhausted immunity Recovery IgM Inflamation Complement RAS Coagulation Edema Fig. 1 High viral load Delayed immune response: •Primoinfection •Exhausted immunity Recovery IgM Therapy: Antivirotics –remdesivir Therapeutical antibodies Therapy: Anti-inflammatory : corticoids Anticoagulant: heparin Inflamation Complement RAS Coagulation Edema Model for deleterious or beneficial effects of corticosteroids in the tr... Model for deleterious or beneficial effects of corticosteroids in the treatment of COVID-19. (A)In asymptomatic or mild cases and in the absence of treatment, SARS–CoV-2 induces transcriptional upregulation of interferons (IFNs) and NF-κB activation, which promote cytokine production and activation of macrophages as well as demargination of PMNs. Antigens are presented to T cells and a targeted cytotoxic response ensues. (B) (B)In worsening illness, corticosteroid treatment can delay pathogen recognition and control. Dampened danger signaling leads to impaired IFN release, unchecked viral replication, and consequent alveolar and lung damage. (C) (C)In severe illness with COVID-19 without corticosteroid treatment, viral propagation to the alveoli amplifies danger signals and worsens alveolar epithelial and endothelial damage. Persistent damage leads to exuberant NF-κB activation and inflammation worsens even as viral load decreases. (D) (D)In severe cases of COVID-19 corticosteroid treatment may decrease proinflammatory cytokine burden and help resolution. Corticosteroids promote a proresolving macrophage phenotype that can clear cellular debris. Corticosteroids also reduce capillary permeability and increase alveolar edema fluid clearance, resulting in improved barrier function. Mechanismy poškození endotelu při infekci SARS-CoV2 Mechanisms of endothelial damage by SARS-CoV2 viral mRNA Covid-19 with solid fill viral mRNA C3b C5b C6 C7 C8 C9 Skull with solid fill C1 complex C2b Vývojový diagram: zpoždění: C4b C4b IgM IgG S-protein C5AR1 (CD88) C5AR2 (GRP77) H2O2 O.