4) Host Defence System

AMPs:

• Anti-microbial peptides, part of the innate immune system

• Abilities:

  • kill pathogens by disrupting their membrane integrity by forming pores in their membrane

  • intracellular toxicity -> kill pathogens by interfering with intracellular processes

• Either bacteriostatic or bactericidal effects

  • bacteriostatic: inhibit growth and reproduction without actually killing the pathogen -> delays further infection

  • bactericidal ->killing pathogens

• also immune modulatory effects

Inflammation (as response to acute bacterial infection):

• Non-specific innate immune response

• Has a rapid onset to clear infections

• Involves soluble factors including complement and phagocytic cells

• Toll-like receptors -> innate immune receptors / sensors that recognice specfic components of the bacterial surface, leading to cytokine secretion and attracting phagocytic cells to the site of infection

• Components:

  • TLR 1, 2, 4 and 6 -> bacterial lipids

  • TLR 9 -> bacterial dna

  • TLR 5 and 10 -> bacterial proteins

• Neutrophils

  • first responders with high antibacterial activity

  • short lives (3-5 days)

  • normally only present in blood

  • attracted to site of infection by several soluble factors (chemotaxis)

  • provide major form of defense against extracellular bacteria

• Macrophages

  • long lived -> months

  • directly kill bacteria through phagocytosis and the production of reactive oxygen and nitrogen intermediates

  • many different types (location + phenotypes

Endocytosis: Cellular process in which substances are brought into the cell

Phagocytosis:

• specific form of endocytosis by which cells internalize solid matter

• including bacterial pathogens

Oxygen-dependent antibacterial activity -> during phagocytosis, the respiratory burst occurs:

• oxygen dependent

• when a phagocyte ingests bacteria: oxygen consumption increases production of oxygen damaging radicales —> which damage the bacterial membrane

• oxygen compounds are toxic to bacteria and host cells —> they are kept in compartments inside cell (=phagosome)

Oxygen-independent antibacterial activity -> phagocytes can also kill bacteria by oxygen independent methods -> not as effective. 4 Main types:

• Damage bacterial membranes via Defensins

• Damage bacterial cell wall via Lysozyme

• Damage bacterial proteins via proteases (cathepsin G, elastase)

• Deprive bacteria of nutrients via Lactoferrin (remove essential iron) or Vitamin B12 binding protein

Requirements:

• phagocytes being attracted to site of infection

• bacteria recognised by the phagocytes

Opsonins:

• chemicals termed opsonins satisify both requirements

• produced in response to bacterial infection

• causes receptor clustering and triggers phagocytosis

• enhance update by phagocytes

• Types:

  • Innate opsonins

  • Acquired opsonins

    • Specific immunoglobulin

Complement cascade

• important for recognition and phagocytosis of opsonised microbes

• series of >20 proteins, circulating in blood and tissue fluids

• most proteins normally inactive

• in response to bacteria —> become sequentially activated in an enzyme cascade

• activation of one protein enzymatically cleaves and activates the next protein in the cascade

• can be archived via 3 different pathways:

  • classical pathway

  • alternative pathway

  • mannose binding lectin (MBL) pathway

Enhance uptake (opsonisation) of bacteria by phagocytes

• by providing neutralization and long-term clearance of bacteria

• this immune response takes up to 7 days to develop effectivly

• crucial for the removel of persistent or chronic bacterial infections

• it is specific and prevents reinfections

• Help B cells make antibodies to specific prozeins/structures

• Help stremgthen/increase cellular response

• CD4 T-cells -> help B cells to produce antibodies that are specific to proteins or structures of bacteria

• TH1 cells -> promote the activation of macrophages and the killing of cells

• TH2 cells -> promote humoral or antibody responses, leading to the proliferation and secretion of antibodies by B cells

• B cells -> center of the adaptive immune system, responsible for mediating the production of antigen-specific immunoglobilin (Ig)

Opsonization:

Neutralization: block/lyse bacteria or deactivate toxins

Agglutination: clump bacteria -> limit growth -> easy target for phagocytes

Complement activation: activate over classical pathway

• Direction modulation: colonization resistensce

  • the gut microbiota provides resistence to colonization by ingested bacteria or inhibits the overgrowth of resident bacteria normally present at low levels

  • archieved by competition for nutrients and niches within the gut, as well as production of antimicrobial substences that inhibit or kill pathogenic bacteria

• Indirect modulation:

  • the microbiota plays a critical role in immune programming

  • it promotes tolerance and boosts specific immune responses

  • this includes strenthening the epithelial barrier, producing short-chain fatty acids (SCFAs) and enhancing the function of various immune cells such as dendritic cells, NK cells, regulatory T cells and mecrophages