Virulence non-specific

• Innate Immunity


  Non-specific Host Defence Mechanisms
• Humans have a Three-Layered Approach to Defence Against Infection

  1. 1

  2. 2

  3. 3
• Timeframe of immune responses


  • 1st - Innate
  • 2nd -Adaptive
  • Innate Magnitude
  • Adaptive Time
• Non-specific (innate) Host Defences


  • Present from birth
  • Not specific to particular pathogens or antigens
  • Always active
  • Instant response to an infectious agent
  • Has no memory
  • Does not improve upon reexposure
  • Involved in the control of Specific (adaptive) immunity
  • Individual components are not very powerful but collectively they exert a very powerful effect
  • Each of the systems will be considered separately but no system works in isolation and physical, chemical, and biological barriers are closely integrated
  • Parts of the innate immune system work also as part of the adaptive immune system
• Non-specific (Innate) Host Defences


  • Physical Barriers
  • Chemical Barriers
  • Biological Barriers
  • General Barriers
• Physical Barriers - Skin


  • Thick layer
  • Difficult to penetrate
  • Keratinised layers of protein
  • Dry
  • Inhospitable to bacteria
  • Continuous replacement of cells
• Physical Barriers - Mucus Membranes


  • Specialised surfaces
  • Intestinal tract
  • Genitourinary tract
  • Respiratory tract
  • Viscous secretions
  • Mucus from Goblet cells
  • Trap microorganisms
  • Continuous replacement of cells
• Physical Barriers - Epithelial Barriers


  • Nasal cavity: filters and baffle plates, slows airflow and traps particles <10 μm
  • Respiratory epithelium: ciliated cells and mucus, traps particles >10 μm which are removed via the mouth and swallowed
  • Intestinal tract: peristalsis, turnover of epithelial cells
  • Genitourinary tract: flushing of urine
  • Conjunctiva: flushing action of tears, blinking
• Circumvention of physical barriers - Skin


  Mechanical damage to integrity; wounds, bites (arthropods, animals, humans) and, increasingly, use of indwelling medical devices
• Circumvention of physical barriers - Respiratory


  • Smoking inhibits action of cilia
  • Drying inhibits action of cilia
  • Ventilation!
  • Virus infection can inhibit action of cilia, allows entry of organisms that would not normally penetrate e.g. bacterial pneumonia following influenza
• Circumvention of physical barriers - Mucus membranes


  • Invading microbes have to possess specialised structures enabling attachment to epithelial cells
  • Mechanisms for invasion are also needed
  • Epithelial cell invasion
  • M cell invasion
• Chemical Barriers - Skin


  • Oleic acid (metabolic by product of Propionibacterium acnes)
  • High salt
  • pH 5-6
  • Low water availability
  • Skin is not a homogeneous environment and the chemical composition of the surface varies depending on the distribution of glands
• Chemical Barriers - Skin cross-section

  • Most of the chemical defence on the skin comes from secretions from the various glands, many of which are associated with hair follicles
• Chemical Barriers - Mucus Membranes


  • Lysozyme (peptidoglycan degradation)
  • Iron binding proteins (Transferrin, lactoferrin)
  • Lactoperoxidase
  • Milk
  • Salivary glands
  • Lungs
• Chemical Barriers - Intestinal Tract


  • pH 2-3 in stomach
  • Bile salts (detergents)
  • Degradative enzymes - proteases, lipases
• Chemical Barriers - Urinary Tract


  • Uric acid/fatty acids
  • Hypertonic environment
• All of the above systems operate to prevent entry of pathogenic microorganisms into the body i.e. they encounter potential invaders external to the epithelial cell layer
• There are a number of systems that operate to eliminate pathogens that have penetrated the primary defences i.e. they encounter invaders in the vascular system or in the tissues
• Complement


  • A set of serum proteins that, when activated, promotes removal of microorganisms by phagocytosis (opsonisation) or by direct killing (membrane disruption)
  • Alternative pathway activation triggered by non-specific signals (Microbial surface polymers, Pathogen Associated Molecular Patterns)
  • Lectin pathway activation (Mannose binding protein)
  • Classical pathway activation triggered by specific signals (antibodies)
• Complement system activation generally involves proteolytic cleavage
• Interferons


  • Family of low molecular weight glycoproteins (cytokines)
  • Exhibit antiviral properties
  • Also have immune regulatory and antibacterial properties
  • INF-alpha produced by lymphocytes
  • INF-beta produced by fibroblasts and epithelial cells, cause cells to produce antiviral proteins that inhibit viral replication
  • INF-gamma produced by T-cells, stimulates neutrophils and macrophages to phagocytose bacteria
• TNF: Tumour necrosis factor


  • Cytokine
  • Released by macrophages and related cell lines following exposure to endotoxin (bacterial lipopolysaccharide)
  • Other biological roles identified (Cancer, Rheumatoid arthritis)
  • Increase vascular permeability allowing phagocytes and complement to more easily reach the site of infection
• Phagocytosis (professional phagocytes)


  • Polymorphonuclear leucocytes (PMNs): short lived cells that monitor tissues and vascular system
  • Macrophages (MOs): long lived cells that monitor tissues
• Mechanism of phagocytosis


  1. Non-specific attachment to particles

  2. Pathogen Associated Molecular Patterns (PAMPs)

  3. Envelopment of particles (phagosomes)

  4. Fusion of phagosome with lysosome (phagolysosome)

  5. Killing of pathogens within phagolysosome: low pH, hydrolytic enzymes, generation of oxygen radicals, generation of reactive nitrogen intermediates, defensins (membrane disrupting peptides)

  6. Different killing mechanisms are in operation in different types of phagocytes
• Normal Microbiota


  • Microbes resident on a host surface may actually play a beneficial role by secreting substances that are toxic to pathogens
  • Propionibacterium acnes on skin releases Oleic acid (product of fatty acid metabolism), inhibitory to gram positive organisms
  • Lactobacillus spp. in vagina release various acids (products of glycogen metabolism), pH 3-5 is inhibitory to most microorganisms especially bacteria
• Inflammation


  • A complex and tightly regulated set of responses triggered by tissue damage and infection
  • Important features: Vasodilation, swelling of local tissues (edema), recruitment of phagocytes to the site of injury/infection by chemotaxis, fibrin clot- activation of complex and tightly regulated set of serum proteins that constitute the clotting pathway
• Classic signs of Inflammation


  • Pain
  • Heat
  • Swelling
  • Redness
  • Altered Function of organ or limb
• General Barriers - Nutrition


  • Malnutrition increases the frequency of all infection especially among younger age groups
  • Integrity of connective tissue challenged
  • Inefficient functioning of phagocytic system
• General Barriers - Age


  • Individuals at both age extremes are very vulnerable to infection
  • Inefficient immune systems as people age (Immunosenescence)
  • Wide variety of effects although acquired immunity more impacted than innate immunity
  • Reduced neutrophil phagocytosis
  • Reduced macrophage chemotaxis
  • Reduced production of cytokines
• General Barriers - Genetic Factors


  • Different human populations are inherently different in their disease responses
  • Malaria is less severe in individuals who are heterozygous for sickle cell anaemia that for individuals that do not even harbour even one copy of the altered gene
  • CCR5 (Cell surface receptor, Reduced HIV binding, 1% of Northern Europeans)
  • CASP12 (Immune response to bacteria, Resistance to sepsis, Most non-Africans)
• General Barriers - Social Factors


  • Clean water supply
  • Adequate sewage disposal
  • Clean and dry living conditions
  • Health education
  • Nutrition education