WEEK 1 INNATE AND PRRs Flashcards
what are 3 strategies the host can adopt to deal with the threat posed by microbes?
- Avoidance
- Resistance
- Tolerance
What do avoidance mechanisms do and what do they include?
- Prevent the exposure to microbes
- Include anatomical barriers and behavioral modifications
What is the aim of resistance in an infection?
- to reduce or eliminate pathogens
What does immunological tolerance refer to?
- ‘mechanisms that prevent an immune response from being mounted against the host’s own tissues’
What is the first,second, third, and fourth line of defense?
- Anatomical barrier on epithelial surfaces (skin, intestine, oral mucosa etc.)
- Complement/antimicrobial proteins (C3, defensins, RegIIIy)
- Innate immune cells (macrophages, granulocytes, NK cells)
- Adaptive immunity (B cells/antibodies, T cells)
What is the basic role of inflammatory inducers?
- They indicate the presence of pathogens or tissue damage
What detects inflammatory inducers?
- Sensor cells e.g. DCs, macrophages, neutrophils (via their innate recognition receptors)
What are examples of inflammatory inducers that trigger innate recognition receptors?
- bacterial LPS
- ATP
What is the precursor for the macrophages, granulocytes, mast cells and DCs of the innate immune system?
- COmmon myeloid progenitor (CMP)
Which cell types do the granulocytes include and what are they aka and why?
- Neutrophils
- Eosinophils
- Basophils
- AKA Polymorphonuclear leukocytes (odly shaped nuclei)
Is the lifespan of granuloctytes short or long?
- Short- only a few days
What does the process of macropinocytosis and which cell type does it occur in?
- Occurs in DCs
- Involves the continuous ingestion of large amounts of extracellular fluid and its contents
What are two categories of inflammatory mediators?
- Cytokines
- Chemokines
Are NK cells lymphocyte like cells?
- YES
Do NK cells have the antigen specific receptors of the adaptive immune cells?
- NO
- But they have the innate receptors that can respond to stress and infections from specific viruses
What is it about the structure of Staph and Strep that makes the bacteria resistant to engulfment by macrophages?
- The polysaccharide capsule
- (Although complement can make the bacteria more susceptible to phagocytosis)
What are the two main compartments where infection can occur?
- Intracellular and exrtacellular
What is an example of facultative intracellular pathogens?
- Mycobacteria - it can replicate either intracellularly or outside the cell
What are two strategies of innate immunity to defend against intracellular pathogens?
- Destroy pathogens before they infect cells (e.g. antimicrobial peptides and phagocytic cells)
- Recognition and killing of cells infected by some pathogens (NK cells check viral infections before the cytotoxic T cells)
What are examples of viruses and bacteria that replicate freely in the cell and viruses that replicate in intracellular vesicles respectively?
- Chlamydia Rickettsia and Listeria (freely in cell)
- Mycobacteria (in intracellular vesicles)
Does the damage caused by an infectious agent depend on where it grows? (provide example)
- YES
- e.g. Strep.pneumoniae in lung causes pneumonia but in the blood it causes sepsis
What are endotoxins known as?
- They are not secreted
- They form part of the bacterial structure
- This structure triggers phagocytes to release cytokines
- This has local and systemic effects
e. g. LIPS of the OCM (gram -ve bacteria) –> fever, pain, rash, septic shock
Are our surface epithelia just a physical barrier to infection?
- NO, they also produce a huge variety of chemical substances. These are microbicidal OR inhibit microbial growth
e. g. acid pH of stomach and all the bile salts, lysolipids etc present in the upper GI
What are the enzymes belonging to the group of antibacterial enzymes that attack the chemical features specific to cell walls?
- Lysozymes
- Phospholipase A2
- these are secreted in the tears and saliva by phagocytes
- Made by paneth cells
What is the mechanism of action of lysozymes?
- It is a glcosidase
- It breaks the chemical bond in peptidoglycan of cell wall
- Specifically it cleaves the beta 1,4 linkage b/w the GlcNAc and MurNAc or peptidoglycan
- Thus more effective against gram +ve bacteria
Lysozymes are secreted by paneth cells. What are paneth cells?
- Specialized cells in the base of crypts in small intestine that secrete many antimicrobial proteins into the gut
What is the rough mechanism of action of phospholipase A2 that can be produced by Paneth cells?
- Basic enzyme that enters the bacterial cell wall to access and hydrolyze the phospholipids in the cell membrane
- This kills the bacteria
What is the second group of antimicrobial proteins secreted by epithelial cells?
- Antimicrobial peptides
What are the three most important classes of antimicrobial peptides?
- Defensins
- Cathelicidins
- Histadins
What are defensins?
- Peptides of around 30-40 aas –> has 3 disulfide bonds stabilizing a common amphipathic structure (+ve charged region separated from hydrophobic region)
- They act to disrupt cell membranes of bacteria and fungi + membrane envelopes of some viruses
What is the mechanism of action of defensins thought to be?
- Insertion of the hydrophobic region into the membrane bilayer
- This forms a pore that makes the membrane leaky
What are the three subfamilies of defensins?
- Alpha
- Beta
- theta
Are defensins generated by propeptides?
- YES
- e.g. developing neutrophils produce alpha defensins by processing an initial propeptide by proteases
Where are the defensins made by neutrophils stored?
- Primary granules
What are alpha defensins produced by paneth cells in the gut called?
- Cryptidins
What are beta defensins primarily made by?
- Skin, respiratory tracts, urogenital tracts, tongue
- In response to presence of microbial products
Are theta defensins active in humans?
- No the gene is inactive in humans but this was present in primates
Are cathelicidins made contitutively (all the time) by neutrophils and macrophages?
- YES
Where is the inactive cathelicidin stored in neutrophils?
-Secondary granules
What are histatins and where are they produced?
- Histidine rich catonic peptides that are active against pathogenic fungi (e.g. Cryptococcus neoformans and Candidia albicans)
- Produced by the oral cavity (parotid, sublingual and submandibular glands)
What 4 main groups are PRRs classified into?
- Free receptors in the serum (e.g. ficolins and histatins)
- Membrane-bound phagocytic receptors
- Membrane bound signalling receptors
- Cytoplasmic signalling receptors
What cell is the major phagocyte population resident in most normal tissues at homeostasis?
- Macrophages
What are macrophages in the liver and neural tissues called respecively?
- Kupffer cells
- Microglial cells
What is the self renewal of Kuffper and microglial cells dependent on?
- IL-34 (cytokine)
In humans, what do 90% of circulating monocytes known as ‘classical monocytes’ express?
- CD14 –> co-receptor for a PRR
What are ‘patrolling monocytes’?
- Roll along endothelium and express Cd14 and CD16 (type of Fc receptor)
What are neutrophils also known as?
- Polymorphonuclear Neutrophillic Leukocytes
What are the two functional types of DCs?
- Conventional (classical) Dendritic Cells
- Plasmacytoid dendritic cells
What is a major role of classical DCs (cDCs)?
- processing ingested microbes to generate peptide antigens that can ACTIVATE T cells to induce an adaptive immune response
- “the bridge b/w innate and adaptive immunity”
What are pDCs?
- Major producers of Type I Interferon (antiviral interferons)
- Considered to be part of innate immunity
What is Dectin-1 and what family is it part of?
- A receptor expressed by macrophages and neutrophils
- recognizes beta1,3 linked glucans –> fungal cell walls
- Part of the C-type lectin family
What does the mannose receptor do and what family is it part of?
- It is expressed by macrophages and DCs and mannosylated ligands (on fungi, bacteria and viruses)
- Clearance receptor on macrophages for host glycoproteins
What do scavenger receptors (on macrophages) recognize?
- Anionic polymers and acetlyated LDLs
- Helps internalize bacteria
What are receptors that stimulate antimicrobial killing?
- GPCRs (G protein coupled receptors)
What is an example of GPCRs in antimicrobial killing?
- The fMLF (fMet-Leu-Phe) receptor (GPCR) that senses the presence of bacteria by their fMet resiude.
- When bacterial polypeptides bind to the receptor, intracellular signalling pathways are initiated and allow cell to move to the most conc. source of ligand
- Also allows ROS to be produced in the phagolysosome
What two things that are activated, are directly involved in the ROS being produced?
- fMLF and C5a
What does NET (Neutrophil Extracellular Trap) require to function?
- Generation of ROS
