4 Host Defence Systems

• body surface as Physical and chemical barrier

• Lysozyme (in tears and saliva) is an enzyme that can kill bacteria

• Anti -microbial peptides (AMPs)

• Rapid onset to clear acute infections

• Non specific

• Mediated by

  • soluble factors including complement phagocytic cells

Toll-like receptors (TLRs)

• TLR1, 2, 4 and 6 recognise bacterial lipids

• TLR9 recognises bacterial DNA

• TLR5 and 10 recognise bacterial proteins

• Activation causes secretion of cytokines

• Attraction of phagocytic cells to infection site

• First responders: accumulate early at site of infection/inflammation

• High antibacterial activity

• Short lived - 3 -4 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 release IL-1 (interleukin 1), IL-6, IL-8 and TNF (tumor necrosis factor)

• Long lived - months

• Attracted to site of infection - mature into phagocytic macrophages in the tissue

  • When activated generate IFN-γ and TNF-α -cause changes to endothelium of blood vessels and act as chemoattractant

• Fixed, e.g., Kupffer cells (liver)

• Mobile, e.g., Alveolar macrophages

• Circulating - Monocytes

bacterial destruction

Respiratory burst is the rapid release of the reactive oxygen species, superoxide anion and hydrogen peroxide, from different cell types.

→ production of oxygen damaging radicles which damage the bacterial membrane

• Reactive oxygen intermediates, ROIs

• Reactive nitrogen intermediates, RNIs

There are 4 main types

• Damage bacterial membranes

  • Defensins, bactericidal/permeability increasing protein (BPI)

• Damage peptidoglycan (bacterial cell wall)

  • Lysozyme

• Damage bacterial proteins

  • Proteases: cathepsin G, elastase

• Deprive bacteria of nutrients

  • Lactoferrin, Lipocalin-2 (remove essential iron from bacteria)

  • Vitamin B12 binding protein

Specific form of endocytosis by which cells internalize solid matter

Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound.

A phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis.

Complement system is a series of >20 proteins, circulating in blood and tissue fluids

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

important for recognition and phagocytosis of opsonised microbes

Enhance uptake (opsonisation) of bacteria by phagocytes

• As result of C3b binding to bacterial cell surface

• C3b (and its breakdown product, iC3b) are recognised by complement receptors (CR) on phagocytic cells

• Enhances engulfment of opsonised particles, leading to intracellular (microbial) killing

TH1 immunity is crucial in bacterial infections – enhances intracellular killing

A granuloma is an aggregation of macrophages that forms in response to chronic inflammation.

Activation of cellular immunity sometimes insufficient to remove bacterial infections

→ when this occurs body naturally seals off infection by the generation of granulomas e.g. Mycobacterium tuberculosis

Activated macrophages

• Enhanced antibacterial activity

• Enhanced respiratory burst

• Production of nitric oxide

• Enhanced phagolysosome fusion

• Enhanced secretion of pro-inflammatory cytokines

• Dependent on bacterial location

• Inhibit interaction between bacterial adhesins and host receptor

  • IgA at mucosal surfaces

  • IgG to stop infection of particular cells types

• Neutralizing antibodies

  • Neutralise effect of particular toxin by preventing binding to specific cell type

    • e.g. anti-tetanus prevents binding to neuronal cells

• mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell, whose membrane-surface antigens have been bound by specific antibodies.

• Antibody allows more effective uptake killing by phagocytes

• Bound antibody acts as an opsonin

  • Efficient killing and uptake via Fc receptor on phagocyte (opsonophagocytosis)

• complement activation results in formation of the membrane attack complex (MAC or C5b -9) that rapidly lyses and kills bacteria

• Activation of C5 results in the release of peptide C5a, a strong chemoattractant that helps to recruit phagocytes towards the site of infection and induces an oxidative burst

Microbiota & infection resistance

• Resistance to colonization by ingested bacteria or inhibition of overgrowth of resident bacteria normally present at low levels within the intestinal tract is called COLONISATION RESISTANCE

  • commensal or pathogenic bacteria

  • First described in the 1950s

  • 100 000-fold decrease in the dose of Salmonella required to infect Germ-Free mice

• Successful colonisation of the intestinal tract represents a difficult task!

  • Both for invading pathogens and beneficial bacteria e.g. ‘probiotic’ Bifidobacterium or Lactobacillus

Microbiota & immune development

• The microbiota plays a critical immune programming role

• Mucosal and systemic immune compartments

• stimulates both ‘tolerance’ and boosts specific responses