Nonspecific Host Defenses in Infection

Bacteria

This section defines the critical elements in combating infectious diseases, emphasizing the significance of nonspecific host defenses.

Nonspecific Host Defenses

Nonspecific host defenses are fundamental in fighting infectious diseases and include various physiological mechanisms that do not target specific pathogens but offer a broader form of protection.

Critical Elements in the Fight Against Infectious Disease

  • Protein in Sweat: A specific protein found in sweat has been shown to inhibit the growth of Lyme disease-causing bacteria in laboratory settings and prevents their infection in mice. However, approximately 40% of individuals possess a mutated form of this protein that is less effective, potentially increasing their susceptibility to Lyme disease infection (as of March 2024).

Chronic Herpesvirus Infections

It is noted that over half of the population is infected with chronic herpesvirus infections. However, severe brain inflammation due to herpesvirus occurs at an extremely low frequency, with a reported incidence of 1 in 250,000 cases. The brain cells have a protein that serves as a barrier preventing the herpesvirus from infecting nerve cells. Cases of herpes encephalitis in two children were associated with a genetic defect affecting this protective mechanism (July 2024).

Interferonopathies

Interferonopathies arise from imbalances in interferon signaling, leading to:

  • Too much: results in severe inflammatory conditions.

  • Too little: increases susceptibility to viral infections.

Learning Objectives

Students should aim to:

  • Explain the role of various nonspecific defenses against infectious diseases, including:
      - Skin
      - Mucous membranes
      - Normal microbiota
      - Interferon
      - Complement
      - Phagocytosis
      - Neutrophil extracellular traps (NETs)
      - Inflammation
      - Fever

  • Recognize the nonspecific defense mechanisms present at major points of pathogen entry.

  • Describe how bacteria circumvent nonspecific defenses.

  • Compare the protective roles of complement and natural killer cells in infection.

Vocabulary

Key terms include:

  • Innate resistance

  • Nonspecific defenses

  • Normal microbiota

  • Transferrin/Lactoferrin

  • Siderophore

  • Interferon

  • Complement

  • Membrane attack complex

  • Opsonization

  • Inflammation

  • Classical pathway

  • Alternate pathway

  • Neutrophil

  • Macrophage

  • Dendritic cell

  • Chemotaxis

  • Phagolysosome

  • Respiratory burst

  • Toll-like receptors

  • Natural killer cell

Innate Resistance

Innate resistance refers to genetic components that grant humans physiological processes that impede compatibility with most plant and animal pathogens. This process occurs because human cells lack the correct receptors necessary for pathogen attachment, and unfavorable temperature and pH values can also diminish pathogen survival.

Host Defenses

Host defenses can be categorized into:

  • Innate defenses: These are nonspecific mechanisms that are present from birth and provide a general defense against various pathogens.

  • Specific adaptive/acquired immunity: These defenses are developed only after exposure to a pathogen and are specific to that particular pathogen.

Nonspecific Defenses

Skin and Mucous Membranes

  • Skin: Acts as a physical barrier, and microbes cannot penetrate intact skin due to its characteristics:
      - Skin is generally dry and cool.
      - The acidity of the skin (low pH) plays a vital role in inhibiting microbial growth.
      - The presence of chemicals such as salt, fatty acids, and lysozymes provides additional protection.
      - Skin microbiota competes against potential pathogens, and lymphoid cells beneath the surface contribute to defense mechanisms.

  • Mucous Membranes: Different from skin; they are moist, warm, and living. Mucous membranes are defended by:
      - Mucus
      - Regular sloughing off of dead cells
      - Chemical defenses
      - Physical movement like peristalsis and ciliary action to aid clearance
      - Internal immune cells and molecules like defensins and antimicrobial peptides (AMPs).

Chemical Defenses

  • Lysozyme: Found in tears, saliva, and vaginal secretions, it breaks down bacterial cell walls.

  • Stomach Acid: Provides a hostile environment for ingested pathogens.

  • Transferrin/Lactoferrin: These proteins bind to iron, depriving bacteria of this essential resource, counteracting bacterial siderophores.

  • Normal Microbiome: Contributes metabolites that combat pathogenic bacteria.

  • Interferon: Stimulates the production of antiviral proteins that act against viral infections, though it is not virus-specific.

Interferon Response and SARS-CoV-2

SARS-CoV-2 is capable of evading the interferon response through several mechanisms:

  • The virus impacts mRNA splicing processes by altering the production of proteins necessary for generating mature mRNA, preventing the translation of proteins that facilitate cellular defenses.

Blood Components

The blood's composition consists of:

  • Plasma: A fluid containing proteins like complement and antibodies.

  • Cells:
      - Erythrocytes (Red Blood Cells): Involved in oxygen transport.
      - Platelets: Assist in clotting reactions.
      - Leukocytes (White Blood Cells): Key players in immune responses.

Complement System

The complement system consists of proteins that reside in the blood, ready to act in defense mechanisms. Advantages of the complement system include:

  • Formation of the Membrane Attack Complex (MAC), leading to cell lysis.

  • Opsonization: Enhances phagocytosis through tagging of pathogens.

  • Recruiting phagocytes for inflammatory responses.

Pathways of Complement Activation

  1. Classical Pathway: Activated by the antibody-pathogen complex.

  2. Alternative Pathway: Initiated by direct binding of complement proteins to the pathogen itself.

Structure of the Classical Pathway

  • Initial components include CI which leads to the formation of C3 convertase that splits C3 into C3a and C3b, contributing to inflammatory response and pathogen targeting.

Bacterial Evasion of Complement

Bacteria utilize various strategies to evade complement activation:

  • Capsules that inhibit complement activation.

  • Lipid-carbohydrate structures on surfaces that prevent MAC formation.

  • Enzymatic digestion of complement components like C5a to disrupt its function.

Immune Cell Types

Leukocytes

  • Basophils: Involved in allergic reactions.

  • Lymphocytes: Essential for specific immunity.

  • Neutrophils and Eosinophils: Engage in phagocytosis of pathogens and can undergo diapedesis (migration through blood vessel walls).

  • Monocytes: Differentiate into macrophages and dendritic cells, crucial for the immune response.
      - Macrophages contain Toll-like receptors that respond to endotoxins and are integral in producing fever (fever benefits include restricting pathogen growth).

Roles of Macrophages

Some macrophages circulate throughout the body, while others are fixed in specific organs. Their primary function is phagocytosis. Specific types include:

  • Alveolar macrophages in the lungs.

  • Microglia in the central nervous system.

  • Küpffer cells in the liver.

Dendritic Cells

These cells are often the first to respond to pathogens at surface interfaces such as the skin and mucous membranes, with capabilities to present antigens to lymph nodes, prompting specific immune responses.

Mechanism of Pathogen Destruction

Phagocytic cells utilize a process called a respiratory or oxidative burst, generating reactive oxygen species (ROS) and nitrogen compounds:

  • Superoxide

  • Hydrogen peroxide

  • Hypochlorite

  • Nitric oxide (NO)
    Alongside degradative enzymes, these components help in pathogen destruction.

Neutrophil Extracellular Traps (NETs)

NETs are specialized defense mechanisms employed by neutrophils to trap pathogens:

  • Neutrophil activation triggers the formation and release of chromatin that ensnares pathogens in a web-like structure, limiting their mobility and facilitating destruction by other immune cells.

Opsonization and Phagocytosis

Opsonins like complement proteins and antibodies enhance the phagocytic process by tagging pathogens:

  • They assist in attachment via nonspecific receptors and through recognized features of the opsonin (Fc receptors and C3b receptors).

Pathogen Survival Tactics

To evade phagocytosis, pathogens may employ various tactics such as:

  • Inhibiting Adherence: Structures like M proteins and capsules, for instance, in bacteria such as Strep pyogenes and S. pneumoniae, hinder phagocyte attachment.

  • Killing Phagocytes: Certain bacteria, like Staphylococcus aureus, can produce leukocidins that destroy phagocytes.

  • Escaping Phagosome: Some bacteria, like Shigella and Listeria monocytogenes, escape the phagosomal compartment to avoid destruction.

  • Preventing Fusion: Pathogens can also prevent the fusion of lysosomes with phagosomes, evading destruction mechanisms. Examples include HIV and Mycobacterium tuberculosis.

Cells Killing Extracellularly

Natural Killer (NK) Cells

NK cells play an essential role in targeting virally-infected and tumor cells:

  • They distinguish infected or abnormal cells based on the presence of MHC class I molecules.

  • Healthy cells express adequate levels of MHC class I to provide inhibition signals that prevent NK cell attack, while diminished expression in abnormal cells leads to activation of NK cell killing via perforin and granzymes inducing apoptosis.

Inflammation

Inflammation serves to localize infections and prevent their spread. It is characterized by:

  • Redness

  • Swelling (edema)

  • Pain

  • Heat
    These symptoms arise due to increased vascular permeability, facilitating the chemotactic movement of phagocytes to the site of infection.

Chronic Inflammation

Chronic inflammation can pose significant health challenges and has been linked to various diseases.