Innate Immunity: Immediate Infection Response

Innate Immunity: The Immediate Response to Infection

• Physical barriers colonized by commensal microorganisms protect against infection.

  • Mammalian babies lack commensals before birth.
  • Commensal microorganisms from the environment (e.g., family members, pets) populate skin and mucosal surfaces after birth.
  • The microbiota is an essential part of a healthy human body, influencing and shaping the development of the immune system (IS).

• Physical, chemical, and microbiological barriers prevent pathogens crossing epithelia and colonizing tissues.

  • Mechanical: Longitudinal flow of air or fluids, e.g., tears, mucus in lungs.
  • Chemical: Low pH, fatty acids, antimicrobial enzymes.
  • Microbiological: Normal microbiota, antimicrobial peptides.
  • Tissues where these barriers exist include skin, gut, lungs, and eyes/nose/oral cavity.

• Intracellular and extracellular pathogens require different immune responses.

  • Extracellular pathogens: Live and replicate in spaces between human cells, accessible to soluble, secreted molecules of the immune system.
  • Intracellular pathogens: Live and replicate inside human cells; host cells must be killed to expose pathogens to soluble immune molecules.
    • Pathogens (bacteria, viruses, fungi, parasites) can be present outside or inside human cells.

Complement System

• Complement is a system of plasma proteins that mark pathogens for destruction.

  • Made by the liver, present in blood, lymph, and extracellular fluid (ECF).
  • Many are inactive zymogens until infection triggers their activation.
  • Complement proteins activate each other in a cascade via proteolytic cleavage.

• Complement activation results in covalent attachment of C3b to pathogen's surface.

  • Cleavage of complement fragment C3 produces a large C3b fragment and a small C3a fragment.
  • C3b is chemically reactive and becomes covalently attached to the pathogen surface, marking it.
  • C3a recruits phagocytic cells to the infection site.

• Three pathways of complement activation exist:

  • Alternative: First pathway to be activated; initiated by direct interaction with the pathogen.
  • Lectin: Part of innate immunity, initiated by mannose-binding lectin in plasma.
  • Classical: Initiated in the innate response by the binding of C-reactive protein to pathogen surfaces; also initiated in the adaptive response by the binding of antibodies to pathogen surfaces.

• Alternative pathway initiates complement activation at the start of an infection.

  • Constituents of bacterial surfaces induce changes in the physiochemical environment, triggering serum C3 hydrolysis.
  • iC3 binds to the inactive complement factor B.
  • Protease (factor D) cleaves factor B, forming iC3Bb, which is a soluble C3 convertase.
  • iC3Bb cleaves C3 into C3a and C3b.
  • C3b fragments covalently attach to the pathogen surface.

• C3 convertase C3bBb works at pathogen surface.

  • Similar to soluble iC3Bb, but is unable to diffuse away because it is bound to a pathogen.

• Regulatory proteins determine the extent and site of C3b deposition.

  • Factor P: extends C3bBb lifetime on microbial surfaces.
  • Factor I: cleaves and inactivates C3bBb (assisted by Factor H).
  • DAF and MCP: disrupt C3bBb on human cell surfaces

Phagocytosis

• Phagocytosis by macrophages provides a first line of cellular defense against invading microorganisms.

  • Macrophages are mature forms of circulating monocytes residing in tissues (e.g., connective tissues, GI & respiratory tracts, liver).
  • Participate in both innate and adaptive immunity.

• Complement receptors on phagocytes trigger C3b-coated pathogen uptake and breakdown.

  • CR1 on macrophages recognizes and binds to C3b-coated pathogens.
  • This recognition generates intracellular signals enhancing phagocytosis.
  • Phagosomes fuse with lysosomes, forming phagolysosomes, leading to the breakdown of the pathogen.

Terminal complement proteins

• Terminal complement proteins lyse pathogens by forming membrane pores.

  • The proteins C5 to C9 assemble the membrane-attack complex (MAC) on the surface of the pathogen.

• This MAC creates pores in pathogenic and eukaryotic cell membranes, leading to cell death.

  • Human cells have a CD59 protein that binds to the C5b678 complex to prevent recruitment of C9 and thus formation of a pore in the cell membrane.

• Small peptides released during complement activation induce local inflammation.

  • C3a and C5a fragments induce inflammatory reactions, called anaphylatoxins.
  • They have receptors on phagocytes, endothelial cells, and mast cells.
  • Roles in inflammation include: increased blood flow, increased vascular permeability, and as chemoattractants.

Other factors

• Several classes of plasma proteins limit infection spread.

  • Coagulation system: Plasma enzymes form blood clots, immobilizing pathogens.
  • Kinin system: Plasma proteins like bradykinin cause vasodilation, increasing the supply of innate immunity components.
  • Protease inhibitors: Inhibitor proteins, like a2-macroglobulins, inhibit pathogenic proteases.

• Antimicrobial peptides kill pathogens by perturbing their membranes.

  • Defensins disrupt microbial membranes by forming pores in the cell membrane.

• Pentraxins are plasma innate immunity proteins that bind microorganisms to phagocytes.

  • Pentraxins play a role similar to antibodies.
  • Two main types are serum amyloid P component (short) and PTX3 (long)

Explore the immediate immune response to infection, focusing on physical barriers and commensal microorganisms. Learn how these barriers, including mechanical, chemical, and microbiological factors, prevent pathogens from colonizing tissues. Understand the different immune responses required for intracellular and extracellular pathogens.