Innate Immunity and Pattern Recognition

Module 1: Innate Immunity Pattern Recognition in Innate Immunity

Instructor: Dr. Daniel Clarke
Department: Microbiology & Immunology, University of Melbourne

Learning Objectives

  • LO1: Explain the basics of innate immune recognition (PRR, danger, altered self)

  • LO2: Understand the ‘Danger Stranger’ model of self vs. foreign/non-self recognition

  • LO3: Discuss compartmentalisation of PAMP recognition by Pattern Recognition Receptors (PRRs) and associated threat levels

  • LO4: Describe the TLR stimulation pathway and associated outcomes

  • LO5: Describe mechanisms involved in RLR, cGAS-STING, and NLR cytosolic receptor signalling

Concepts of Innate Immune Recognition

  • The immune system must distinguish between external stimuli and self to respond appropriately.

  • Innate Immunity involves recognizing both ‘non-self’ (foreign pathogens) and ‘damaged self’ molecules (DAMPs).

  • The traditional view was that immunity relied solely on recognizing non-self substances that trigger immune responses.

  • Charles Janeway's hypothesis: Suggested shared receptors (PRRs) can detect common structures of microbial pathogens.

Key Features of PRRs

  • Primitive Pattern Recognition Receptors (PRRs) are found in innate immune cells like dendritic cells, macrophages, and neutrophils.

  • PRRs serve to detect PAMPs (Pathogen-Associated Molecular Patterns) and DAMPs (Damage-Associated Molecular Patterns).

Definitions

  • PAMPs: Conserved molecular patterns found in microbes that signal non-self

  • DAMPs: Components released by host cells during cell damage or death that indicate trouble within the host

Danger-Stranger Model of Recognition

  • This model describes how the immune system distinguishes between harmful entities (danger) and harmless entities (stranger) by recognizing self and non-self.

Compartmentalisation of PRR Recognition

Locations and Associated Threat Levels

  • Extracellular (Cell Membrane):

    • #### PRRs: TLR1, TLR2, TLR4, TLR5, TLR6

    • Targets: Bacteria, Viruses, Parasites

  • Intracellular-Vesicular (Phagosomes/Endosomes):

    • #### PRRs: TLR3, TLR7, TLR8, TLR9

  • Cytosolic:

    • #### PRRs: RLRs, NLRs

    • Targets: Cytoplasmic components of Bacteria and Viruses

TLR Stimulation Pathway and Outcomes

  • TLR4 Example:

    • Recognizes bacterial lipopolysaccharide (LPS) in the presence of accessory proteins (MD-2, CD14).

    • Activation Steps:

    • Binding leads to MyD88 recruitment

    • Activation of IRAK4 and TRAF6

    • IKK activation leads to IκB degradation and NFκB release

    • NFκB enters the nucleus, activating inflammatory cytokine genes

Cytosolic PRR Signalling Mechanisms

  • RLRs: Detect viral RNA in the cytosol, induce secretion of inflammatory cytokines and IFNs.

  • cGAS-STING Pathway: cGAS binds to dsDNA, producing cGAMP which activates STING, leading to IFN synthesis.

  • NLR Cyclic Activation:

    • Inactive NOD proteins become activated upon ligand binding

    • Recruitment of RIP2 activates pathways leading to NFκB activation for inflammation

    • Inflammasome formation leading to IL-1β production and pyroptosis

Conclusions

  • Germ-Line Encoded PRRs are crucial for recognizing foreign patterns.

  • The immune system uses PRRs for detection of vital traits of pathogens (PAMPs) and altered self molecules (DAMPs).

  • Compartmentalisation enables distinct cellular responses based on pathogen location.

  • Membrane-bound PRRs are integral for MyD88-mediated NFκB activation and inflammatory cytokine production.

  • Cytosolic PRRs inform immune responses to intracellular infections, with some triggering inflammasome activation leading to acute inflammatory responses.