Microbiology: The Innate Immune Response Study Notes

Introduction to Innate Immunity

  • Host Environment and Microbes: To microbes, the human body is a nutrient-rich environment. However, the interior of the body is generally sterile.
  • Innate Immunity: This represents the routine protection that is present at birth.
  • Adaptive Immunity: This form of immunity develops throughout life as the body is exposed to microbes or foreign material.
  • Antigens and Antibodies: Antigens stimulate the production of antibodies, which bind to the antigens and target them for destruction. This system can also destroy infected host cells or "self" cells.

Overview of Innate Immune Defenses

  • First-line Defenses: These act as barriers blocking entry into the body.
  • Sensor Systems: If invaders breach the first-line barriers, sensor systems detect them.
    • Sentinel Cells: These cells use pattern recognition receptors (PRRs) to identify unique microbial components.
    • Complement System: This system is found in both the blood and tissue fluid.
  • Innate Effector Actions: These actions are designed to destroy invaders.
    • Interferon (IFN): This is a protein secreted during viral infections.
    • Phagocytes: These cells engulf microbes or cell debris through a process called phagocytosis.
    • Inflammatory Response: A coordinated response to infection or tissue damage.
    • Fever: This interferes with pathogen growth and enhances other immune responses.

First-Line Defenses: Physical Barriers

  • Epithelium: All exposed surfaces of the body are lined with epithelium. These borders are categorized as being outside or inside the body.
    • Outside: The skin serves as the primary external barrier.
    • Inside: Mucous membranes line the digestive tract, respiratory tract, and urogenital tract.
  • Skin Characteristics:
    • The skin is difficult for microbes to penetrate.
    • Dermis: Composed of tightly woven fibrous connective tissue.
    • Epidermis: Composed of many layers of epithelial cells. The outermost layers are dead and filled with keratin. This environment repels water, stays dry, and continually flakes off, removing any attached microbes.
  • Mucous Membranes:
    • These line the digestive, respiratory, and genitourinary tracts and are constantly bathed in secretions such as mucus.
    • Mechanisms exist to move microbes toward areas for elimination:
      • Peristalsis: The rhythmic contractions of the intestines.
      • Mucociliary Escalator: Ciliary action in the respiratory tract that removes microbes.

First-Line Defenses: Antimicrobial Substances

  • Salt: Accumulates on the skin from perspiration.
  • Lysozyme: An enzyme that degrades peptidoglycan.
  • Peroxidases: Enzymes that break down hydrogen peroxide to form antimicrobial compounds.
  • Iron-Binding Proteins: Lactoferrin and transferrin bind iron, making it unavailable to microbes.
  • Antimicrobial Peptides (AMPs): Small proteins like defensins that form pores in microbial membranes.

First-Line Defenses: Normal Microbiota (Flora)

  • Competitive Exclusion: Pathogens are excluded by the microbiota covering binding sites and consuming available nutrients.
  • Production of Toxic Compounds:
    • Cutibacterium species degrade lipids and produce fatty acids.
    • E. coli synthesizes colicins in the intestinal tract.
    • Lactobacillus in the vagina produces a low pH environment.
  • Disruption of Microbiota: Use of antibiotics can predispose a person to infections by disrupting normal flora, such as Clostridium difficile in the intestine or Candida albicans in the vagina.
  • Immune Development: The normal microbiota is essential to the proper development of the immune system.

Cells of the Immune System

  • Hematopoiesis: The formation and development of blood cells.
  • Hematopoietic Stem Cells: All blood cells originate from these cells, which are found in the bone marrow.
  • Colony-Stimulating Factors (CSFs): These induce the development of stem cells. Blood cell numbers increase during infections.
  • General Categories of Blood Cells:
    • Red Blood Cells (Erythrocytes): Carry O2O_2.
    • Platelets: Derived from megakaryocytes; involved in clotting.
    • White Blood Cells (Leukocytes): Important for host defenses. These are categorized into granulocytes, mononuclear phagocytes, and lymphocytes.

Types of White Blood Cells (Leukocytes)

  • Granulocytes: Named for their staining properties and cytoplasmic granules, which are released via degranulation.
    • Neutrophils: Engulf and destroy bacteria; contain enzymes and antimicrobials. Also called polymorphonuclear neutrophilic leukocytes (PMNs). Their numbers increase during infection.
    • Basophils: Involved in allergic reactions and inflammation; granules contain histamine.
    • Mast Cells: Similar to basophils but found in tissues rather than blood.
    • Eosinophils: Fight parasitic worms and are involved in allergic reactions; granules contain antimicrobials and histaminase.
  • Mononuclear Phagocytes: Part of the mononuclear phagocyte system (MPS).
    • Monocytes: Circulate in the blood.
    • Macrophages: Differentiate from monocytes after they leave the bloodstream. They serve as sentinel cells found in nearly all tissues.
    • Dendritic Cells: Sentinel cells that act as "scouts." They engulf material in tissues and bring it to cells of the adaptive immune system for "inspection."
  • Lymphocytes: Responsible for adaptive immunity.
    • B Cells and T Cells: Highly specific in their recognition of antigens; generally reside in lymph nodes and lymphatic tissues.
    • Innate Lymphoid Cells (ILCs): Lack specificity; can promote the inflammatory response.
    • Natural Killer (NK) Cells: A type of ILC that destroys certain types of cells.

Cell Communication

  • Surface Receptors: Serve as the "eyes" and "ears" of the cell. They span the membrane to connect the outside to the inside. Binding to a specific ligand induces a response.
  • Cytokines: Act as the "voices" of the cell. Produced by one cell, they diffuse to others and bind to receptors to induce growth, differentiation, movement, or cell death. They act at low concentrations and can have local, regional, or systemic effects.
  • Adhesion Molecules: Allow cells to adhere to other cells. For example, endothelial cells use them to grab phagocytic cells to allow them to exit the bloodstream.

Major Cytokine Groups

  • Chemokines: Induce chemotaxis of immune cells.
  • Colony-Stimulating Factors (CSFs): Manage the multiplication and differentiation of leukocytes.
  • Interferons (IFNs): Control viral infections and regulate immune responses.
  • Interleukins (ILs): Produced by leukocytes; critical for both innate and adaptive immunity.
  • Tumor Necrosis Factor (TNF): Involved in inflammation and apoptosis.
  • Pro-inflammatory Cytokines: Include TNF, IL-1, and IL-6.
  • Cytokine Storm: A potentially deadly overproduction of cytokines during an immune response, notably seen in COVID-19.

Pattern Recognition Receptors (PRRs)

  • Function: Allow the body to "see" signs of microbial invasion and lead to cytokine secretion.
  • Target Patterns:
    • Microbe-Associated Molecular Patterns (MAMPs): Components like peptidoglycan, lipoteichoic acid, lipopolysaccharide (LPS), lipoproteins, flagellin subunits, and microbial nucleic acids.
    • Pathogen-Associated Molecular Patterns (PAMPs): Specific to pathogens but not exclusive to them.
    • Damage-Associated Molecular Patterns (DAMPs): Indicate host cell damage.
  • Locations of PRRs: Found on the cell surface, in endosomes and phagosomes, and free in the cytoplasm.
  • Specific Receptor Types:
    • Toll-Like Receptors (TLRs): Anchored in membranes. Surface TLRs monitor the extracellular environment; TLRs in organelles characterize ingested material.
    • C-Type Lectin Receptors (CLRs): Found in dendritic cells along with TLRs.
    • RIG-Like Receptors (RLRs): Cytoplasmic receptors that detect viral RNA (often double-stranded and lacking a cap).
    • NOD-Like Receptors (NLRs): Cytoplasmic receptors detecting microbial components or cell damage. In macrophages or dendritic cells, they combine with other proteins to form an inflammasome.

The Interferon (IFN) Response

  • Mechanism: PRRs detect viral RNA, inducing the cell to produce IFN.
  • Antiviral Proteins (AVPs): IFN causes neighboring cells to express inactive antiviral proteins (iAVPs).
  • Activation: iAVPs are activated by viral double-stranded RNA (dsRNA). Once activated, they degrade mRNA and stop protein synthesis, leading the infected cell to undergo apoptosis.

The Complement System

  • Overview: A series of proteins (C1 through C9) circulating in blood and tissue fluid that "complement" adaptive immunity.
  • Activation Pathways:
    • Alternative Pathway: Triggered when C3b binds to foreign cell surfaces.
    • Lectin Pathway: Mannose-binding lectins (MBLs) bind to mannose on microbial cells.
    • Classical Pathway: Activated by antibodies bound to antigens.
  • C3 Convertase: All pathways lead to the formation of C3 convertase, which splits C3 into C3a and C3b.
  • Major Outcomes:
    • Opsonization: C3b binds to bacterial cells, functioning as an opsonin that promotes engulfment by phagocytes.
    • Inflammatory Response: C5a attracts phagocytes; C3a and C5a increase vascular permeability and induce mast cells to release cytokines.
    • Lysis of Foreign Cells: C5b combines with C6, C7, C8, and C9 to form Membrane Attack Complexes (MACs) that insert into the cell membranes of Gram-negative bacteria.
  • Regulation: Host cell membranes bind regulatory proteins that inactivate C3b to prevent the host's own cells from being targeted.

Phagocytosis Process

  1. Chemotaxis: Phagocytes are recruited by chemoattractants (microbial products, phospholipids from injured cells, chemokines, C5a).
  2. Recognition and Attachment: Can be direct (receptors bind mannose) or indirect (binding to opsonins).
  3. Engulfment: Pseudopods surround the material to form a phagosome.
  4. Phagosome Maturation and Phagolysosome Formation: Directed by TLRs, the phagosome fuses with lysosomes containing enzymes.
  5. Destruction and Digestion: Toxic reactive oxygen species (ROS) and nitric oxide are produced; pH decreases; enzymes degrade material; lactoferrin binds iron.
  6. Exocytosis: The vesicle fuses with the membrane to expel remains.

Phagocyte Characteristics

  • Macrophages: Described as everyday "beat cops."
    • They phagocytize dead cells and debris and live for weeks or months.
    • M1 Macrophages: Have greater killing power.
    • M2 Macrophages: Function to lessen inflammation.
    • Giant Cells: Formed by the fusion of macrophages if they alone are insufficient.
    • Granulomas: Consist of macrophages, giant cells, and T cells. They wall off organisms (like those causing Tuberculosis) to prevent escape, though they interfere with tissue function.
  • Neutrophils: Described as the "SWAT team."
    • They are the first to be recruited to the site of damage for a rapid response.
    • They are powerful but short-lived (1−21-2 days in tissues), dying once their granules are used.
    • Neutrophil Extracellular Traps (NETs): Neutrophils can release DNA to catch microbes, allowing granules to destroy them.

The Inflammatory Response

  • Purpose: Contain the site of damage, localize the response, eliminate the invader, and restore tissue function.
  • Symptoms: Swelling, redness, heat, pain, and sometimes loss of function.
  • The Inflammatory Process:
    • Vascular Changes: Diameter of blood vessels increases due to histamine; blood flow slows. Pro-inflammatory chemicals cause capillaries to become leaky.
    • Exudate: Protein-rich fluid (containing transferrin, complement, antibodies) leaks into tissue, causing swelling and pain.
    • Cellular Changes: Endothelial cells "grab" phagocytes.
    • Diapedesis: Phagocytes squeeze between dilated vessel cells into tissues.
    • Clotting: Clotting factors wall off the site to stop bleeding and the spread of microbes.
  • Outcomes:
    • Acute Inflammation: Short-term, mainly involving neutrophils and macrophages.
    • Chronic Inflammation: Occurs if acute fails; results in granulomas and giant cells.
    • Pus and Abscess: Pus is an accumulation of dead neutrophils and tissue debris. A localized collection of pus is an abscess.

Damaging Effects of Inflammation and Cell Death

  • Collateral Damage: Like a fire sprinkler system, inflammation prevents spread but harms the structure. Enzymes and toxic compounds from phagocytes can damage tissues, which is especially dangerous in the brain or spinal cord.
  • Autoimmune Diseases: Can cause unwarranted chronic inflammation, such as Rheumatoid Arthritis leading to joint damage.
  • Associations: Chronic inflammation is linked to some cancers and types of obesity.
  • Types of Cell Death:
    • Necrosis: Traumatic cell death due to damage.
    • Apoptosis: Programmed cell death; does not trigger inflammation.
    • Pyroptosis and Necroptosis: Types of programmed self-destruction that specifically trigger an inflammatory response to sacrifice infected cells.

Fever

  • Definition: An indicator of infection, particularly bacterial. An oral temperature above 37.8 ∘C37.8\,^{\circ}\text{C} is regarded as a fever.
  • Mechanism: The brain's temperature-regulation center (normally set at 37 ∘C37\,^{\circ}\text{C}) raises the temperature in response to pyrogens.
  • Pyrogens: Fever-inducing cytokines that can be produced by the body or by microbes.
  • Benefits:
    • Bacterial growth rates drop above their optimum (37 ∘C37\,^{\circ}\text{C}).
    • Increases the rate of enzymes.
    • Enhances inflammatory responses, phagocytic activity, and lymphocyte multiplication.
    • Enhances production of interferons, antibodies, and the release of leukocytes from bone marrow.