Unit Three Lecture: Microbial Pathogenicity and Host Defenses

Unit Three: Curriculum Objectives and Overview

• 15 Microbial Pathogenicity

  • 15.1 Infectious Disease

  • 15.2 Virulence and Infection

• 17 Innate Nonspecific Defense

  • 17.1 Physical Defenses

  • 17.2 Chemical Defenses

  • 17.3 Cellular Defenses

  • 17.4 Pathogen Recognition

  • 17.5 Inflammation and Fever

• 18 Adaptive Specific Defense

  • 18.1 Humoral, Cellular, and Antibodies

  • 18.2 Major Histocompatibility Complex (MHC)

  • 18.3 Cellular Response

  • 18.4 Humoral Response

  • 18.5 Vaccines

• 19 Diseases of the Immune System

  • 19.1 Hypersensitivities

  • 19.2 Autoimmune Disorders

  • 19.3 Organ Rejection

  • 19.4 Immunodeficiency

  • 19.5 Cancer Immunobiology

• Organ-Specific Infections

  • 21 Skin and Eye Infections

  • 22 Respiratory Infections

  • 23 Urogenital Infections

  • 24 Digestive Infections

  • 25 Circulatory and Lymphatic System Infections

  • 26 Nervous System Infections

Patterns of Disease and Pathogenicity

• Predisposing Factors for Disease:

  • Etiologic Agent: Characteristics including Pathogenicity (Virulence Factors), Mode of Dissemination, Reservoir Host, Host Specificity, and Dose.

  • Host Susceptibility: Influenced by Age, Chronic Disease status, Nutrition, Genetic Factors, Non-Specific and Specific Defenses, Behavior, and Personal Education.

  • Disease Transmission: The mechanisms by which a pathogen moves between hosts.

  • Environment: External conditions impacting host susceptibility.

• Portals of Entry:

  • Integumentary System: Entry via wounds, injuries, or other breaches in the skin.

  • Mucous Membranes: Includes the Conjunctiva of the eye, Digestive System (Oral Cavity), Respiratory System (Nasal Cavity), and Urogenital/Reproductive Systems.

  • Other Entry Points: Tear ducts and the external ear canal.

• Stages in the Development of Disease:

  • Incubation Period: Time between infection and the appearance of the first signs and symptoms; remains contagious; duration depends on the specific disease.

  • Prodromal Period: Characterized by early, mild symptoms often described as "I’m coming down with something."

  • Illness: Overt signs and symptoms are present; individual is most contagious. This stage involves the battle between the pathogen and the host's medicine/immunity.

  • Decline: Signs and symptoms begin to subside; risk of secondary infections; individual feels they are "getting better, but not $100\%$."

  • Convalescence: Returning to the pre-disease state; the individual may still be a contagious carrier.

Overview of Host Defenses

• First Line of Defense (Innate, Nonspecific): Surface protections composed of anatomical and physiological barriers that prevent microbes from penetrating sterile body compartments.

  • Physical barriers.

  • Chemical barriers.

  • Genetic components.

• Second Line of Defense (Innate, Nonspecific): A cellular and chemical system that activates immediately if agents pass surface defenses.

  • Inflammatory response.

  • Interferons.

  • Phagocytosis.

  • Complement system.

• Third Line of Defense (Acquired, Specific): Long-term immunity developed uniquely for each microbe with memory. Involves specialized white blood cells (WBCs).

  • Antibodies, B cells, T cells, accessory cells, and cytokines.

The First Line of Defense: Physical and Chemical Barriers

• Non-specific Innate Barriers:

  • External Ear Canal: Cerumen (earwax) maintains a $pH$ of $3$ to $5$.

  • Eye Conjunctiva: Tears provide mechanical rinsing and contain Lysozyme and Lactoferrin.

  • Mechanical Defenses: Blinking (eyelashes/eyelids) and general hygiene.

  • Cellular Junctions: Tight junctions and desmosomes create physical seals between cells.

  • Mucous Membranes: Line body cavities to trap and expel contaminants.

  • Antimicrobial Peptides (AMP): Chemical defenses present on surfaces.

• The Microbiome:

  • Composition: Bacteria make up $99\%$ of the microbiome with a ratio of $1$ microbe to $1$ eukaryote cell. Profiles are unique, evolve over time, and vary by diet, environment, and lifestyle.

  • Protection: Colonization begins at birth; prevents pathogen growth and trains the immune system.

  • Metabolism: Aids in digestion and maintains a symbiotic relationship without producing disease.

  • Microbiome Disruption: Caused by widespread over-use of antibiotics, processed food diets (low fiber), and chronic stress. Leads to inflammation, malabsorption, immune dysfunction, and gut-brain axis issues (e.g., nosocomial infections in immunocompromised patients).

Innate Defense of Body Systems

• Integumentary System (Skin):

  • Anatomy: Avascular covering consisting of Epidermis, Dermis, and Hypodermis. Epidermal layers (from bottom to top) are Stratum basale, Spinosum, Granulosum, Lucidum, and Corneum.

  • Physical Barriers: Keratin protein is tough and resistant. The Stratum Corneum consists of $15$ to $40$ layers of dead cells that shed constantly and are sealed with a "glue" of fatty acid chains and cholesterol.

  • Chemical Defenses: Skin has a $pH$ of $4.7$ to $5.7$ (acid mantle), moisturized by urea and amino acids. Glands secrete Dermcidin (sudoriferous) and Sebum (sebaceous). Proteins like Defensins and moisturizing factors are produced in the Stratum Granulosum.

  • Microbiota: Includes Archaea, Bacteria (Staphylococcus spp., Corynebacterium spp., Cutibacterium spp., Micrococcus spp., Streptococcus spp.), Fungi (Candida spp., Malassezia spp.), and Arthropods (Demodex spp. mites in hair follicles).

• Respiratory System:

  • Physical/Mechanical Barriers: Mucus, nasal hair, sneezing, coughing, and the mucociliary escalator (cilia).

  • Chemical Defense: Surfactant, Defensins, and Lactoferrin.

  • Microbiota: Archaea; Bacteria such as Prevotella spp. ($10$ to $20\%$), Streptococcus spp. ($10$ to $15\%$), Veillonella spp. ($5$ to $10\%$), Haemophilus spp. ($5$ to $10\%$), and Fusobacterium spp. ($5$ to $10\%$); Fungi such as Malassezia spp. (< 5\%) and Candida spp. (< 1\%); and Bacteriophage viruses.

• Urinary System:

  • Mechanical Defense: Periodic urine flow.

  • Chemical Defense: $pH$ range of $4.5$ to $8.0$. Urothelial cells produce Defensins, Lysozyme, and Lactoferrin.

  • Microbiota: Varies by sex. Lactobacillus spp. is higher in females ($20$ to $60\%$) than males (< 10\%). Also includes Gardnerella spp. ($10$ to $30\%$ in females), Prevotella, Streptococcus, Malassezia, Candida, and Bacteriophages.

• Digestive System:

  • Physical Barriers: Villi and microvilli, tight junctions, and the largest/most diverse gut microbiome.

  • Mechanical Defenses: Peristalsis, stomach churning, segmentation, and vomiting.

  • Chemical Defenses: Saliva contains IgA, Lysozyme, and Lactoferrin. Stomach $pH$ is $1.5$ to $3.5$ (enzyme Pepsin). Paneth cells in the small intestine produce Defensins. Microbiome in the large intestine produces butyric acid (from soluble fiber) and vitamins B and K.

  • Microbiota:

    • Oral: Streptococcus ($\sim 20\%$), Prevotella, Veillonella.

    • Stomach: Helicobacter pylori.

    • Small Intestine: Lactobacillus spp. ($16$ to $20\%$), Enterococcus spp. ($8$ to $15\%$).

    • Large Intestine: Bacteroides spp. ($30$ to $50\%$), Clostridium spp. ($30$ to $50\%$), Bifidobacterium spp. ($10$ to $20\%$), Faecalibacterium prausnitzii ($5$ to $15\%$).

The Second Line of Defense: Cellular and Systemic Responses

• The Liver: Filters pathogens via Kupffer cells; detoxifies metabolic waste and cellular debris; stores glucose as glycogen and micronutrients (Vitamins A, D, E, K; Minerals $Fe$, $Cu$); performs protein anabolism for clotting factors, complement proteins, and acute-phase proteins.

• Cardiovascular Barriers: Endothelial layers with tight junctions; the Blood-Brain Barrier (increased strength tight junctions). Chemical defenses include Cathelicidins, Defensins, and Nitric Oxide.

• Inflammatory Response:

  1. Vasoconstriction: Immediate response to initiate a blood clot.

  2. Chemical Release: Mast cells and damaged tissues release Histamine (causing vasodilation and leaky venules), Cytokines, and Prostaglandins.

  3. Margination: Leukocytes adhere to the wall of the vessel.

  4. Diapedesis: Neutrophils and monocytes squeeze through vessel walls into tissue.

  5. Chemotaxis and Phagocytosis: Cells follow chemical signals to engulf and destroy bacteria and dead cells.

  6. Healing: Growth factors from WBCs and platelets stimulate cell division.

• Fever (Systemic Response):

  • Triggered by cytokines and prostaglandins to increase body temperature, inhibit microbial growth, and enhance immune response.

  • Dangerous Level: > 105^\circ\text{F}\: (40.7^\circ\text{C}) causing tissue damage.

  • Lethal Level: > 108^\circ\text{F}\: (42^\circ\text{C}) causing organ damage.

• Cytokines:

  • Regulate immunity, inflammation, and hematopoiesis. Produced by lymphocytes and endothelial cells.

  • Interleukins: For cell communication, activation, and differentiation.

  • Chemokines: Facilitate chemotaxis (movement).

  • Interferons: Provide antiviral protection.

• Complement System:

  • Circulate as precursor proteins activated in a cascade via Classical (antibody-bound), Lectin (mannose-binding), or Alternative (pathogen surface) pathways.

  • Outcomes:

    • Membrane Attack Complex (MAC): Forms a pore (components $C_5b$ through $C_9$) that causes cell lysis.

    • Opsonization: $C_3b$ binds to pathogens to enhance phagocytosis.

    • Inflammation: $C_3a$ and $C_5a$ serve as anaphylatoxins.

• Acute Phase Proteins: Rapidly amplify immune responses (e.g., Fibrinogen, Ferritin, C-Reactive Protein, Serum Amyloid A).

Anatomy of the Lymphatic System

• Function: Interstitial fluid recovery, dietary fat absorption ($1$ to $2\%$), and leukocyte distribution.

• Lymph: Clear/yellowish fluid ($95\%$ water, $2$ to $3\%$ protein) that flows unidirectionally away from tissues.

• Primary Lymphoid Organs: Bone Marrow (leukocyte production) and Thymus (T lymphocyte maturation). The thymus is largest in childhood and shrinks with age as it is replaced by adipose tissue.

• Secondary Lymphoid Organs:

  • Lymph Nodes: ($500$ to $700$ in the body) filter lymph and host antigen presentation. B cells reside in the Cortex; T cells in the Paracortex.

  • Spleen: Filters blood in the White Pulp; recycles RBCs and stores erythrocytes/thrombocytes in the Red Pulp.

  • Tonsils: Trap pathogens in crypts. Include Pharyngeal, Palatine (paired), and Lingual tonsils.

  • MALT: Mucous-Associated Lymphoid Tissue (includes the Vermiform Appendix).

Cellular Defenses and Hematopoiesis

• Hematopoiesis: The body produces roughly $100$ billion leukocytes per day in the bone marrow. All cells derive from a multipotential hematopoietic stem cell.

• Mast Cells: Sentinels that release Histamine and Cytokines to initiate inflammation.

• Granulocytes: Most abundant leukocytes characterized by specialized granules.

  • Neutrophils: Most abundant ($40$ to $70\%$); first responders to bacteria; multilobed nuclei ($3$ to $5$ lobes); contain lysozymes.

  • Eosinophils: ($1$ to $4\%$); target helminths (worms) and assist in allergic responses; red-orange granules.

  • Basophils: (< 1\%); target allergens; release large amounts of Histamine; dark granules.

• Agranulocytes:

  • Monocytes: Largest WBC; differentiate into macrophages and dendritic cells.

  • Macrophages: Ubiquitous tissue resident cells; Kidney-shaped nucleus; specialized in phagocytosis and antigen presentation.

  • Dendritic Cells: Specialists in antigen presentation to T lymphocytes.

• Natural Killer (NK) Cells: Large granular lymphocytes ($7$ to $13\%$ of circulating lymphocytes). Destroy virus-infected and tumor cells.

• Major Histocompatibility Complex (MHC):

  • MHC Class I: Found on all nucleated cells; presents abnormal proteins to activate cytotoxic T cells.

  • MHC Class II: Found on Professional Antigen Presenting Cells (APCs) — Macrophages, Dendritic cells, and B cells — to activate helper T cells ($CD_4^+$).

Phagocytosis Process

1. Chemotaxis: Movement toward chemical signals.

2. Adherence: Recognition of Pathogen-Associated Molecular Patterns (PAMPs).

3. Endocytosis: Engulfing the pathogen.

4. Phagolysosome Formation: Fusion of phagosome with lysosome ($pH\: 4$ to $5.5$).

5. Digestion: Use of Superoxide, $H_2O_2$, and Lysozyme.

6. Exocytosis: Release of debris and antigen presentation.

Third Line of Defense: Adaptive Immunity

• General Characteristics: Highly targeted protection involving B and T lymphocytes ($15$ to $25\%$ of WBCs) with specificity and memory.

• B-Lymphocytes (Humoral Immunity):

  • Maturation: Produced and matured in red bone marrow. Maturity stages: Immature, Naive (mature but not activated), and Activated (Effector).

  • Activation: Requires specific antigen recognition, endocytosis, and confirmation from a $CD_4^+$ Helper T cell via cytokines.

  • Differentiation: Activated B cells become Plasma cells (releasing $2000$ antibodies/second) or Memory B cells (stored in secondary lymphoid organs).

  • Antibody Anatomy: Heavy chains (Constant region defines class) and Light chains. Both have a Variable Region that recognizes the specific Epitope via hydrogen/ionic bonds and Van der Waals forces.

• Antibody Classes (Immunoglobulins):

  • ${IgG}$: Most abundant ($75\%$); monomer; crosses the placenta; provides long-term immunity; half-life of $21$ days.

  • ${IgA}$: Dimer ($15\%$); found in secretions (tears, saliva, mucus); protects mucosal surfaces; half-life of $4$ to $6$ days.

  • ${IgM}$: Pentamer ($10\%$); first responder; strong agglutination and complement activation.

  • ${IgD}$: Monomer ($0.25\%$); serves as a surface receptor on immature B cells.

  • ${IgE}$: Monomer ($0.0005\%$); mediates allergic reactions (binds mast cells/basophils) and targets helminths.

• Immune Response Timing:

  • Primary Exposure: Lag phase of $4$ to $7$ days; Low magnitude of ${IgM}$ and ${IgG}$.

  • Secondary Exposure: Lag phase of $1$ to $3$ days; High magnitude of ${IgG}$ ($10$ to $100\times$ higher); robust and long-lasting.

• Vaccines and Immunity:

  • Naturally Acquired: Active (infection) or Passive (maternal antibodies/milk).

  • Artificially Acquired: Active (vaccination) or Passive (immune serum/antibodies).

  • Vaccine Types: Live Attenuated, Inactivated, Toxoid (bacterial toxins), Subunit (recombinant/conjugate), and mRNA.

  • Herd Immunity: Community protection depends on pathogen transmissibility, duration of immunity, and mutation rate.

• T-Lymphocytes (Cellular Immunity):

  • Maturation: Mature in the Thymus. Selection involves Positive selection (MHC interaction) and Negative selection/Tolerance (self-recognition).

  • ${CD_4^+}$ Helper T Cells: Master coordinators. ${Th_1}$ activates macrophages; ${Th_2}$ promotes ${IgE}$; ${Th_{17}}$ recruits neutrophils.

  • Regulatory T Cells (Tregs): Suppress immune response to prevent collateral damage and maintain tolerance ($CD_{25}^+$ expression).

  • ${CD_8^+}$ Cytotoxic T Cells: Identify and destroy infected or malignant cells using Perforins and Granzymes.

Persistent Infections and Portals of Exit

• Autoimmune Diseases: Examples include Addison disease, Celiac disease, Type I Diabetes, Graves disease, Hashimoto thyroiditis, Multiple Sclerosis, Myasthenia Gravis, Psoriasis, Rheumatoid Arthritis, and Systemic Lupus.

• Viral Persistence:

  • Latent: Dormant, DNA integration, inactive in tissues, asymptomatic.

  • Chronic: Ongoing replication and symptoms, leading to immune fatigue.

  • Cancer Link: Long-term viral presence can cause DNA damage, activate oncogenes, or inactivate tumor suppressors.

• Portals of Exit: Pathogens leave the body via the Respiratory tract (cough/sneeze), GI tract (saliva/feces), Genitourinary tract (urine/secretions), Arthropod vectors, or Syringes.