Immune Response to Bacterial Infection

Gram Staining

Gram staining is a common way to group bacteria, dividing them into gram-positive and gram-negative based on their cell wall structure.

Gram-Positive Bacteria

• Stain: Purple color after Gram staining.

• Cell Wall: Thick peptidoglycan layer that retains the primary dye.

Gram-Negative Bacteria

• Stain: Pink color after Gram staining.

• Cell Wall: Thin peptidoglycan layer located in the periplasmic space between two membranes. They cannot retain the primary dye.

• Lipopolysaccharide (LPS): Present in the outer membrane, acts as a potent virulence factor.

Bacterial Pathogenesis

Steps for Bacteria to Cause Disease

1. Adherence: Bacteria adhere to the surface of the skin or mucosal surfaces.

2. Invasion: Bacteria invade into cells or between cells, entering tissues.

3. Toxin Production: Some bacteria produce toxins.

Types of Toxins

• Exotoxin: Secreted toxins that can be detected in the supernatant of bacterial cultures.

• Endotoxin: Component of the bacteria that induces inflammation; LPS in gram-negative bacteria is a typical endotoxin.

Site of Infection

Pathogens are divided into extracellular and intracellular infections.

Extracellular Infections

• Interstitial Space: Pathogens found between cells within tissues.

• epethelial surfaces: Pathogens that inhabit the layers of cells lining various organs and body cavities.

• Solution: Pathogens carried in blood or lymph.

• Mucosal Surface: Pathogens stay on the mucosal surface, causing infection.

Intracellular Infections

• Cytoplasm: Pathogens reside inside the cytoplasm of cells.

• Vesicle: Pathogens reside inside the cytoplasm, wrapped in a vesicle (e.g., Mycobacterium tuberculosis).

General Strategy of Immune Response

1. Pathogen Contact: Bacterial pathogen contacts a new host.

2. Colonization/Penetration: The pathogen colonizes on the surface or penetrates into tissues or cells.

3. Innate Immune System: The innate immune system responds first.

4. Adaptive Immune System: If the innate immune system cannot clear the pathogen within three days, the adaptive immune system mounts an immune response.

Time Frame for Immune Response

• Innate Immune Response: Immediate.

• Adaptive Immune Response: Detectable effectors after 5-7 days. (e.g., antibody)

• Secondary Response: Much faster due to memory cells.

• Immune responses are regulated (e.g., interleukin-10, T regulatory T cells).

Innate Immune Receptors

Surface Receptors

• Detect extracellular pathogens.

• Examples include:

  • Lectin-like receptors (detect polysaccharides).

  • Toll-like receptors (TLRs 1, 2, 4, 5, 6).

  • Formyl peptide receptor (detects formyl group on bacterial peptides).

Intracellular Receptors

• Detect intracellular pathogens.

• Example: NOD receptors (detect dipeptide).

Secreted Receptors

• Some lectins are secreted and bind to carbohydrates on pathogens.

• These receptors facilitate phagocytosis, inflammation, and complement activation.

Inflammation

• Macrophages secrete cytokines, causing inflammation.

• Inflammation: Molecular mechanisms include complement activation, increased vascular permeability, and recruitment of immune cells.

• Complement Pathways: Initiated by antibody-antigen complexes or direct pathogen activation (Alternative Pathway).

Adaptive Immune Response

• B cells produce antibodies; T cells have different subsets.

• Occurs in secondary lymphoid organs.

• Bacteria have millions of base pairs, encoding many proteins and sugars.

• When immune response is induced, chronoselection and chronosepansion select B cells or T cells best match the epitopes on the bacteria.

• Multiple clones of B and T cells are involved, not a single cell activation.

B Cell Activation

T-Dependent Antigens

• Induce high-quality, high-affinity antibodies.

• Require help from T follicular helper cells (Tfh).

• Tfh cells are a subset of CD4+ T cells that help B cells in the germinal center.

• B cells present antigens via MHC class II to Tfh cells.

• Tfh cells provide additional signals like CD40 ligand interaction with CD40 receptor on B cells.

• Tfh cells produce cytokines like interleukin-21 and interleukin-4 to stimulate B cells.

T-Independent Antigens

• Activate B cells without T cell help.

  • Type 1 (TI-1): Have repetitive structures like LPS or bacterial DNA, activate B cells through toll-like receptors (TLRs).

    • Mainly induce IgM production.

  • Type 2 (TI-2): Have highly repetitive structures like bacterial capsules, cross-link B cell receptors.

    • Mainly induce IgM production.

  • Marginal zone B cells in the spleen respond well to TI-2 antigens.

T Cell Responses

T cells require multiple signals for activation.

• Signal 1: Antigen presentation by MHC molecules (which were activated from dendritic cells)

• Signal 2: B7 interaction with CD28 on T cells.

• Signal 3: Cytokines (IL 6, IL 12, IL 23, IL 4)

Different T cell subsets play different roles in controlling bacterial infections.

• Th1 Cells: Help macrophages, particularly in intracellular infections like Mycobacterium tuberculosis.

  • Macrophages present antigen to Th1 cells, which secrete interferon-gamma to activate macrophages and enhance killing of intracellular bacteria.

• Th2 Cells: Involved in antibody production and class switching.

• Th17 Cells: Important in mucosal defense against bacterial infections; they recruit neutrophils and produce antimicrobial peptides.

• T Follicular Helper (Tfh) Cells: Help B cells in the germinal center, promoting antibody production.

• T Regulatory (Treg) Cells: Inhibit immune responses to regulate and prevent excessive inflammation.

Effector Mechanisms

The most effective effector molecules differ for different pathogens.

Extracellular Pathogens

• Interstitial Space: Antibodies, complement, and phagocytosis are important.

• Epithelial Surface: IgA antibodies are crucial.

Intracellular Pathogens

• Cytoplasm: NK cells and cytotoxic T cells kill infected cells.

• Vesicle: T cell-dependent macrophage activation (Th1) is important; NK cells can also help.

Skin Infection Example

• Skin's barrier protects against infection; normal flora includes Staphylococcus epidermidis.

• Cut allows bacteria to enter tissue, activating resident macrophages and dendritic cells.

• Macrophages phagocytose pathogens and produce cytokines, initiating inflammation.

• Dendritic cells migrate to lymph nodes to present antigens to T cells, activating the adaptive immune system.

• Effector molecules like antibodies and T cells c ome back to the infection site to clear the pathogen.

Systemic Infection

• If local infection is not controlled, bacteria can enter the blood, causing systemic infection.

• The spleen plays a key role in filtering blood and providing an environment for interaction between antigens, B cells, T cells, and dendritic cells.

• Red blood cells with complement receptor one (CR1) bind to C3b-antigen-antibody complexes and carry them to the spleen for clearance.

• enlarged liver and spleen

Persistent Infection

• The immune system controls but cannot eliminate the pathogen; a typical example is Mycobacterium tuberculosis.

• Macrophages engulf bacteria but cannot kill them, so they call for help from T cells.

• Th1 cells produce interferon-gamma to enhance macrophage activity.

• The infection is contained within a granuloma called a tubercle, with macrophages and T cells surrounding the bacteria.

Outcomes of Infection

• Infection Resolved: Cleared by innate or adaptive immunity.

• Patient Dies: Particularly in severe blood infections.

• Persistent Infection: The pathogen is controlled but not eliminated.

Interaction Between Innate and Adaptive Immunity

• Innate and adaptive immunity do not work alone but interact with each other.

• Dendritic cells (innate) present antigens to T cells (adaptive).

• Cytokines produced by innate cells help T cell development.

• Antibodies (adaptive) activate complement (innate).

• Cytokines secreted by T cells (adaptive) activate macrophages (innate).