Innate Immune System

Agenda for Today

• The schedule includes a welcome and agenda overview for 5 minutes.
• Two minutes are allocated to learning outcomes.
• Interactive lecture is scheduled for 43 minutes.

Learning Outcomes

• Various components of the innate immune system, including physical barriers, recognition proteins, cells, and cellular defenses work together to detect and respond to broad classes of pathogens.
• Different pathogen evasion strategies, such as lysosomal resistance, are evaluated and compared to propose modifications to innate immune mechanisms that could counteract these evasions.
• The complement system, interferons, and antimicrobial peptides contribute to the innate immune response and support pathogen elimination.

The Immune System

• Pathogens like bacteria, fungi, and viruses seek nutrients and transport within an animal's body.
• The immune system protects against pathogens, preventing infections.
• The first line of defense includes physical barriers like skin, shells, and secretions.
• Barrier limitations arise from openings needed for gas exchange, nutrition, and reproduction.
• Immune cells detect foreign particles and activate defenses if a pathogen breaches barriers.
• Molecular recognition allows immune cells to differentiate between self and nonself.
• Two types of immunity exist: innate and adaptive.
• Innate immunity is common to all animals and provides general protection.
• Adaptive immunity is found only in vertebrates and involves specialized molecular and cellular responses.

Innate Immunity

• Innate immunity provides immediate, non-specific protection against pathogens.
• Physical, chemical, and biological barriers are part of innate immunity.
• The cellular response involves macrophages, neutrophils, natural killer (NK) cells, and dendritic cells to destroy pathogens.
• Mast cells release histamine during the inflammatory response, causing swelling, redness, and attraction of immune cells.
• Toll-like receptors (TLRs) are used for pattern recognition, detecting common microbial patterns.
• Unlike adaptive immunity, innate immunity has no memory and does not provide long-term protection.

Insect Immunity

• Highlights the success of invertebrates in pathogen-rich environments.
• Exoskeletons, made of chitin, act as a physical shield.
• Chitin-lined intestines prevent infection.
• Lysozyme enzymes in the digestive system break down bacterial cell walls.
• Insect immune cells produce recognition proteins to bind pathogen molecules.
• Acting as identity tags for pathogen recognition.
• Binding triggers an innate immune response.
• Some hemocytes perform phagocytosis, ingesting and breaking down microorganisms.
• Some hemocytes release defense molecules that entrap larger pathogens like Plasmodium.
• Others secrete antimicrobial peptides that circulate and kill bacteria/fungi by disrupting plasma membranes.

Barrier Defenses in Mammals

• Mucous membranes line the digestive, respiratory, urinary, and reproductive tracts, producing mucus that traps pathogens.
• Ciliated epithelial cells in airways move mucus upward, preventing lung infections.
• Saliva, tears, and mucous secretions wash exposed surfaces, reducing bacterial and fungal colonization.
• Lysozyme is found in tears, saliva, and mucus and breaks down bacterial cell walls.
• Stomach acid (pH 2) kills most ingested pathogens.
• Skin secretions, such as oil and sweat glands create an acidic environment (pH 3-5), inhibiting bacterial growth.
• Microbiome is a biological defense.

Toll-like Receptors (TLRs)

• Toll-like receptors (TLRs) can be found in mammals
• TLRs that are phagocytic, are part of the innate immune system, ingest, and destroy pathogens
• These cells use specific receptors that allow them recognize viral, fungal, or bacterial components
• TLR's bind to pathogen-specific molecular fragments, triggering immune responses:
• TLR3 binds double-stranded from certain viruses and are inside vesicles
• TLR4 recognizes Lipopolysaccharides (LPS) from bacterial surfaces and are found on immune cell plasma membranes
• TLR5 recognizes flagellin, the primary protein of bacterial flagella

Scientists create TLR4 knockout mouse

• Consequence: An impaired ability to detect and respond to bacterial infections is the most likely consequence for the mouse
• This is because TLR4 recognizes LPS, a key component of Gram-negative bacteria

Three Phagocytic Cells

• Neutrophils circulate in the blood, are attracted to infected tissues, engulf, and destroy them.
• Macrophages are larger, migrate or reside in organs/tissues like the spleen.
• Dendritic Cells engulf pathogens and present antigens to T cells, linking innate and adaptive immunity.
• All three contribute to immune defense, with neutrophils and macrophages focusing on pathogen destruction. Dendritic cells specialize in antigen presentation.

Eosinophils

• Eosinophils are located in mucosal tissues
• They defend against parasites by releasing toxic granules and enzymes
• Also contribute to allergies and asthma-related tissue damage

Natural Killer (NK) Cells

• Natural killer (NK) cells patrol blood and lymph, detecting virus-infected or cancerous cells.
• Eliminate cells via apoptosis using perforins and granzymes.
• Perforins and granzymes offer early immune defense.

Mast Cells

• Mast cells are in connective tissues near blood vessels and lungs
• They release histamine and inflammatory mediators
• They also drive vasodilation, immune cell recruitment, and allergic responses

Local Inflammatory Response

• Triggered by injury or infection, and leads to swelling, redness, and warmth.
• Mast cells release histamine, causing capillary dilation and increased permeability.
• Macrophages secrete cytokines, attracting neutrophils to the site.
• Neutrophils and other immune cells enter tissues to destroy pathogens and clear debris.
• Increased blood flow delivers antimicrobial peptides to kill or inactivate pathogens.
• Pus forms from dead white blood cells, pathogens, and damaged tissue.
• The lymphatic system absorbs excess fluid and pus, transporting it to lymph nodes.
• Macrophages in lymph nodes engulf pathogens, while dendritic cells stimulate adaptive immunity.

Cytokines

• Signaling proteins are released by immune cells.
• Bind to cytokine receptors on target cells to cause specific immune responses.
• Regulate inflammation by promoting (pro-inflammatory) or suppressing (anti-inflammatory) responses.
• Recruit immune cells, such as neutrophils, through chemokines.
• Coordinate innate and adaptive immunity, aiding communication between immune cells.
• Examples include Interleukins (ILs) for cell signaling, Interferons (IFNs) for antiviral defense and Tumor necrosis factors (TNFs) for inflammation.

Systemic (Spread) Inflammation

• Occurs when inflammation spreads throughout the body due to extensive tissue damage or infection.
• Injured tissues release molecules that stimulate neutrophil production in bone marrow.
• Severe infections (e.g., meningitis, appendicitis) can cause a rapid increase in white blood cells.
• Fever is a common response, triggered by substances from activated macrophages, possibly enhancing phagocytosis and tissue repair.
• When the immune system detects an infection, macrophages release signaling molecules, or cytokines.
• These cytokines travel through the bloodstream to the hypothalamus in the brain, regulating body temperature.
• The hypothalamus raises the body's temperature set point, leading to fever.

Sepsis and Cytokine Storms

• Sepsis constitutes an extreme inflammatory response that if left untreated, leads to an infection, and damage to internal organs
• COVID-19-related sepsis can damage blood vessels, cause clotting issues, and lead to respiratory failure.
• Blood vessel leakage in sepsis causes swelling and low blood pressure.
• Septic shock occurs if blood pressure drops severely and has a mortality rate above 40%.
• Cytokine storms result from an excessive cytokine release, leading to severe tissue damage.

Chronic (Prolonged) Inflammation

• Prolonged, unregulated inflammation can damage tissues and organs.
• Crohn's disease and ulcerative colitis result from chronic immune activation, disrupting intestinal function, or Inflammatory Bowel Diseases (IBD).
• Autoimmune diseases include rheumatoid arthritis (RA), where chronic inflammation in joints leads to pain, swelling, and joint damage. Lupus is a widespread inflammation that affects organs, skin, and joints.

Antimicrobial Peptides and Proteins: Key Points

• Pathogen recognition triggers the release of proteins that attack pathogens or inhibit reproduction.
• Interferons are secreted by virus-infected cells to signal nearby cells to produce antiviral substances, limiting viral spread.
• Some white blood cells release interferons to activate macrophages for enhanced pathogen destruction.
• Used in medicine (e.g., for hepatitis C) through recombinant DNA technology.
• The complement system consists of 30 blood plasma proteins that remain inactive until activated by pathogen molecules.
• Activation triggers a cascade reaction, leading to pathogen lysis and aiding inflammation and the immune response.

Evasion of Innate Immunity by Pathogens

• Some bacteria evade phagocytosis by producing protective outer capsules that prevent immune recognition, such as Streptococcus pneumoniae which causes pneumonia and meningitis.
• Other bacteria resist destruction inside host cells, like Mycobacterium tuberculosis, surviving and replicating within immune cells, leading to tuberculosis (TB).
• Viruses block innate immunity by encoding proteins that suppress host protein synthesis or inhibit interferon production, allowing infections to establish before an immune response can occur.

Immune Response Scenario Question 1

• Macrophages and neutrophils engulfing bacteria at the wound is the most critical in preventing bacterial infection at the wound site initially.
• Mast cells releasing histamine helps recruit immune cells but does not directly eliminate bacteria initially.
• The complement system tagging bacteria aids in pathogen recognition but still relies on phagocytes for destruction.
• Skin cell regeneration helps seal the wound but does not eliminate bacteria already inside.

Immune Response Scenario Question 2

• Neighboring cells will remain unprotected, allowing faster viral spread is the most likely consequence as without interferons, nearby cells fail to activate antiviral responses, making it easier for the virus to spread
• Cells do not engulf viruses; instead, they rely on interferons to slow viral replication and signal the immune system.
• The adaptive immune response takes days, whereas interferons provide an immediate innate defense.
• Fever is regulated by pyrogens, not interferons, so a lack of interferons does not prevent fever.