Innate Immune Responses Flashcards
What does innate immunity involve?
- Antimicrobial peptides
- Phagocytosis
- NK cells
- Interferons
- Complement system
- Acute inflammatory response
What are the host defences in order?
- Anatomical and chemical barriers- skin, mucus, antimicrobial peptides in mucus
- Intrinsic immunity
- Innate immunity
- Aquired immunity
Outline intrinsic immunity
Always present in uninflected cells
• Apoptosis, autophagy, RNA silencing, antiviral proteins
• Cellular proteins that inhibit viral replication (TRIM, APOBEC3, Tethering)
What are permissive and non-permissive cells?
Whether they allow viral infection within themselves
Which cellular proteins inhibit viral replication?
TRIM
APOBEC3
Tetherin
What are the soluble mechanisms of innate immunity?
• Antimicrobial enzymes (lysozymes) and Antimicrobial proteins (defensins, cathelicidins, histatins)
—> present in skin (from keratinocytes and epithelial cells) and in cell granules
• Complement, cytokines, acute phase proteins
Outline defensins
• Small cationic (+ve) antimicrobial peptides
• Kill bacteria, fungi, some viruses
• Insert into negatively charged membrane to create holes
• Widely expressed (leukocytes and epithelium), intracellular and secreted
• Two structural families
- α-Defensins- constitutively expressed
- β-Defensins- Some induced (by lipopolysaccharide LPS)
Outline innate cellular responses
Respond to threat or communicate to other cells
• must distinguish infectious agents from commensals, self-antigens and environmental antigens- present auto/allergy
• Pattern recognition receptors (PRRs) recognise pathogen-associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs)
Outline antigen recognition
Innate:
• about 1000 molecules can be recognised, <100 types of receptor
• germ-line encoded so limited diversity
Adaptive:
• recognises specific epitopes
• >10^7 molecules recognised, 2 receptor types- TCR and antibody
• Somatic recombination so huge diversity
Outline pattern recognition receptors PRRs
Soluble molecules: • pentrexins (eg CRP) • collectins (eg mannose binding lectin) • ficolins • complement proteins- recognise lipopolysaccharides (LPS) or terminal sugars on microbial cell wall
Cell-associated molecules:
• cell surface (C-type lectins, TLR 2,4,5, scavenger receptors on phagocytes)
• endosome/phagosome (some TLRs- 3,7,8,9- recognise nucleus acids not wall)
• cytosolic (NOD-like receptors NLRs, RIG-like receptors, c-GAS)- sense DNA in cytoplasm- damage
Outline the function of Toll-like receptors TLRs
Major group of PRR
Ligand engages TLR
- > association of protein kinases to adaptor proteins
- > activation of transcription factors
- > respiratory burst, cytokines, chemokines, MMPs, antimicrobial peptides, expression of costimulatory molecules (APCs)
Give examples of TLRs
Plasma membrane: • TLR2- bacterial lipopeptides and lipoproptein • TLR4- bacterial LPS • TLR5- bacterial flagellin —> IRF, NFκB (B cell activation)
Endosomal:
• TLR3- viral dsDNA
• TLR7+8- viral ssRNA nucleotide analogues
• TLR9- bacterial unmethylated CpG DNA
—> IRF (interferon regulatory factor)/NFκB
Outline the classes of PRR
• NOD-like receptors (NLRs)
- NOD1/2 recognise peptidoglycans in bacterial cell wall to prevent escape from phagosome
- NLRP3 forms part of inflammasome and recognises bacterial products and DAMPs (ATP, ROS)
- RIG-like receptors- recognise viral RNA (RIG1, MDAS)
- Cytosolic DNA sensors- recognise microbial DNA in cytoplasm (c-GAS/STING pathway)
What are the cells of innate immunity and what do they do?
- Macrophages
- Dendritic cells
- Polymorphonuclear leukocytes (neutrophils, eosinophils, basophils)
- mast cells
- NK cells (borderline innate/adaptive)
—> Phagocytosis, inflammation, cytotoxicity
Outline phagocytosis
• Neutrophils first to respond, then monocytes enter tissue and become macrophages
- Chemotaxis/scavenger molecule recognition of pathogen
- Adherence via PAMP recognition
- Cell activation via PRR
- Phagocytosis initiation- encloses pathogen
- Phagosome formation
- Phagolysosome formation- joining to lysosome
- Enzymes, pH, killing of bacteria (respiratory burst-> O2 dependent killing- ROS and RNS generated)
- Release of degradation products