INNATE IMMUNITY II

Intracellular killing Reminder PHAGOCYTOSIS Phagocyte PRR Degradation ACTIVATION Bacterium Uptake Intracellular killing Antigen presentation T cell ACQUIRED IMMUNITY Antigen + Antibody ACQUIRED IMMUNITY 0.5 - 1 hours The amount of internalized particles is limited

Complement-dependent COMPLEMENT ACTIVATION Reminder Bacterium COMPLEMENT Lectin pathway Alternative pathway Lysis of bacteria Complement-proteins Inflammation Chemotaxis Complement-dependent phagocytosis Antigen + Antibody ACQUIRED IMMUNITY Few minutes – 1 hour Enzymes get fragmented, complement activity can be exhausted

INFLAMMATION – ACUTE PHASE RESPONSE Reminder neutrophil TNF- DANGER SIGNAL ACTIVATION PRR Bacterium LPS cytokines TNF- IL-1 IL-6 Few hours ACUTE PHASE RESPONSE NK-cell IL-12 macrophage IFN hrs Plasma level LPS (endotoxin) (Gram(-) bacteria) TNF- IL-1 IL-6 Kinetics of the release of pro-inflammatory cytokines in bacterial infection

NK cells

RECOGNITION OF ALTERED HOST CELLS ACTIVATION OF NATURAL KILLER CELLS NK-CELLS Virus-infected cell PRR RECOGNITION ACTIVATION Lysis of infected cell RECOGNITION OF ALTERED HOST CELLS Kinetics of the activity of the complement system and NK cells in virus infection IFN IL-12 Complement system NK-cells days Relatív szint/aktivitás

Adaptive components are also able to activate NK cells ADCC-Antibody Dependent Cell Cytotoxicity Activating NK cells through FcR on NK cells recognizing pathogen-bound Antibodies

INTERFERON RESPONSE

EFFECTS OF TYPE I INTERFERONS NATURAL INTERFERON PRODUCING CELLS – IPC vírus Plasmacytoid dendritic cells produce 1000x more type I interferon than other cells NATURAL INTERFERON PRODUCING CELLS – IPC After viral infection they are accumulated at the T cell zone of the lymph nodes

VIRUS INDUCED TYPE I INTERFERON PRODUCTION Type I IFN receptor IFN response Virus IFN- IRF-3 NFB AP-1 IRF-3 IFN- paracrine IFN- IRF-7 autocrine TLR3 binds dsRNA, IRF3 gets phosphorylated, dimerizes and translocate into the nucleus. IFN-beta expression is induced. Autokrine and paracrine effects. Infected cell IFN response IFN- subtypes IRF: interferon regulatory factor

GAS – promoter elements Type I. IFN receptor Type III. IFN receptor (IFNλ) Type II. IFN receptor IFNAR1/2 IFNLR1 IL-10R2 IFNG1/2 TYK2 JAK1 TYK2 JAK1 JAK2 JAK1 Plasma membrane Cytoplasm Signal Transducers and Activators of Transcription STAT1 STAT1 STAT2 ISGF-3 STAT1 STAT2 P STAT1 P PKR. Ser/thr protein kinase activated by ds RNA. Autophosphorylactivated by dsRNAation and also eIF2. Translation shut off. OAS: activated by ds RNA. 2’5’ oligo A syntehsized, RNAse L is dimerized and activated. ssRNA is cleaved. GAS: Gamma activating sequence IRF9 Interferon-stimulated genes Nucleus STAT1 P STAT1 STAT2 P ISG15, Mx, OAS and PKR GAS: Gamma Activating sequence ISRE GAS – promoter elements Antiviral immunity Interferon-stimulated Regulatory elements Antimycobacterial immunity

INTERFERON EFFECTOR PATHWAYS induction of the „antiviral state 1. Mx GTPase pathway block viral transcription 2. 2',5'-oligoadenylate-synthetase (OAS)-directed Ribonuclease L pathway degrade viral RNA 3. Protein kinase R (PKR) pathway (Ser/Thr kinase, dsRNA-dependent) inhibit translation 4. ISG15 ubiquitin-like pathway modify protein function CONTROL ALL STEPS OF VIRAL REPLICATION

Mechanism of action of MxA, OAS1 and PKR cleaved RNA Oligomer accumulation in cytoplasmic membranes (e.g. ER) (Nucleus) (Cytoplasm) ISRE MxA MxA monomer MxA oligomer Trapped viral components Mechanism of action of MxA, OAS1 and PKR (Nucleus) (Cytoplasm) ISRE PKR Inactive PKR monomer Active PKR dimer Induction by viral RNAs EIF2a P Inhibition of translation (Nucleus) (Cytoplasm) ISRE OAS1 Inactive OAS1 monomer Induction by viral dsRNA Active OAS1 tetramer synthetized pppA(2’p5’A)n inactive RNaseL monomer active dimer cleaved RNA

MULTIPLE EFFECTS OF TYPE I INTERFERONS on immune cells Increased cytotoxicity and proliferation of NK-cells TLR4 TRAM TRIF TLR7 TLR8 TLR9 TLR3 TRIF MyD88 TANK IRAK-1 Activation of - and γδ T-cells TRAF-6 RIG-1 IKKε TBK1 IRF-7 IRF-3 IRF-5 IFN-β, IFN-α1 Increased antigen presentation in myeloid dendritic cells IRF-7 Type I interferon receptor Stimulation of Ig-production in B-cells