Antibacterial Response

Introduction

• Humans have three basic lines of defense against infection: blocking entry, stopping spread, and preventing colonization.
• Natural barriers include skin, mucus, ciliated epithelium, and gastric acid.
• Innate defenses provide rapid, non-antigen-specific immunity.
• Adaptive defenses are antigen-specific but take longer to develop.

Antibacterial Responses

• Successful breaching of physical barriers by bacteria activates innate and inflammatory responses locally.
• This progresses to acute-phase and antigen-specific responses systemically, including fever and body aches.
• The innate immune system involves inflammation and antiviral responses and is not mutually exclusive, if viruses infect cells then released into the extracellular

Initiation of Antibacterial Response

• Bacterial components like LPS and PGN initiate the response.
• Pathogen-associated molecular patterns (PAMPs) are bacterial components.
• Cytokine production and dendritic cell maturation occur.
• Cytokines are released from damaged tissue.
• The complement system acts as an early response, activating inflammation and killing bacteria directly.
• protective factors are released after the inflammatory repsonse is initiated

Complement System

• Chemotactic factor C5a attracts neutrophils and macrophages.
• Anaphylotoxins C3a and C5a stimulate mast cells, increasing vascular permeability.
• Opsonin C3b promotes phagocytosis.
• B-cell activation from C3d

Inflammation

• Cardinal signs include heat, pain, redness, and swelling
• Opsonins act as a "siracha sauce" for the cell.

Complement Activation

• The complement system activates through three pathways, leading to C3b production.
• C3b initiates inflammation-stimulating peptides and the membrane attack complex (MAC).
• The MAC creates holes in plasma membranes, leading to cell lysis.

Chemotaxis and Leukocyte Migration

• Chemokines create a "runway" to guide cells to the infection site.
• Endothelial cells lining capillaries express adhesion molecules.
• Leukocytes slow down, roll, attach, and extravasate (diapedesis).

Phagocyte Responses

• Microorganisms are delivered to a lysosome via membrane-enclosed vesicles.
• Oxygen-independent killing involves lysozyme, phospholipase A2, ribonuclease, deoxyribonuclease, and proteases.
• Oxygen-dependent killing produces toxic reactive oxygen and nitrogen intermediates such as NO.

Phagocytosis

• Splenic macrophages clear bacteria from the blood, especially encapsulated bacteria.
• Asplenic individuals are highly susceptible to infections.

Cytokine-Induced Responses

• PAMPs stimulate dendritic cells and macrophages to release IL-1, IL-6, and TNFα.
• These promote fever and enhance inflammatory responses, triggering the acute-phase response.

Acute-Phase Response

• Triggered by IL-1, IL-6, TNFα, inflammation, and tissue injury.
• Leads to fever, anorexia, sleepiness, and metabolic changes.

Acute-Phase Proteins

• Production increases, supporting host defenses.
• C-reactive protein complexes with bacterial polysaccharides and activates complement.
• Other components include complement and coagulation proteins, and LPS-binding proteins.

Acute Inflammation

• An early defense mechanism to control infection spread and signal specific immune responses.
• Involves capillary expansion, increased microvasculature permeability, and neutrophil recruitment.

Inflammatory Cascade

• Activation of extracellular enzyme kallikrein cleaves and activates bradykinin.
• Bradykinin binds to capillary wall receptors, opening junctions and stimulating mast cells.
• Histamine is released, and prostaglandin production is stimulated, causing pain.

Cardinal Signs of Inflammation

• Characteristics include heat, pain, redness, and swelling.

Chronic Inflammation

• A slower process often resulting in permanent tissue damage.
• Bacterial persistence can cause chronic inflammation and dense lymphocyte infiltration.

Adaptive Immune Response

• CD4+ TH1 T-cells activate epithelial cells and neutrophils and produce antimicrobial peptides.
• Important for early antibacterial responses.
• Stimulate and reinforce inflammatory responses and are essential for combating intracellular bacteria.

CD4+ TH2 T-cells

• Initiated and sustained by B-cells responses
• T2 cells secrete IL-4, IL-5, IL-6, IL-10, and IL-13, enhancing B-cell differentiation and IgG production.

Immunoglobulin Isotypes

• There are different types of Antibodies (IgA, IgD, IgE, IgG, IgM) that all have different funcitons in the body
• The type of Immunoglobulin that circulates blood stream in the body during infection is the result of recycling mechanism
• Immunoglobulin and antibody is the same

Antibody Responses

• First exposure to an antigen causes a slower, primary immune response.
• Second exposure results in a rapid, amplified secondary response due to memory cells.

Bacterial Immunopathogenesis

• Activation of inflammatory/acute-phase responses can damage tissue and cause systemic damage.
• Antibodies that share determinants can cause cross reactivity with human autoimmune proteins.
• Cytokine storm (uncontrolled release of cytokines).

Bacterial Immunopathogenesis - Shock

• Pyrexia (fever) occurs due to increased cytokine levels.
• Systemic vasodilation leads to hypotension. (low blood pressure)
• Warm, sweaty skin is a result of vasodilation.
• Systemic leukocyte adhesion occurs to endothelial tissue.

Bacterial Evasion

• Mechanisms include: inhibition of phagocytosis
• Intracellular killing in the phagocyte and inactivation of complement function

Granuloma Formation

• Involves formation of granulomas that contains Mycobacterium tuberculosis

Antiviral Responses

• Host defenses against viral infection includes interferons like NK cells
• CD4 TH1 responses
• CD8 cytotoxic T-cells are involved

Natural Killer (NK) Cells

• Kill infected/injured cells by releasing perforin and granzymes.
• Secrete IFNy, increasing the capacity of macrophages to kill phagocytosed bacteria and directing the differentiation of T-cells into TH1 cells.

Interferon (IFN)

• Interferon is the body's first active defense against viral infection
• Type 1 includes Alpha (α) and beta (β)
• Type 2 includes Gamma (y)Macrophage activating factor

Interferons and Antiviral State

• IFN-a and IFN-ẞ induce and release, preventing antiviral function
• Protein kinase R (Antiviral State)

Cell-Mediated Immunity

• Interferons stimulate activating effector cells
• Interferons enhance recognition of cells

Antiviral Responses - Humoral Immunity

• Antibody blocks progression
• Cell-Mediated Immunity includes CD4-TH1 which is generally more important for controlling infections

Respiratory Syncytial Virus (RSV)

• Innate starts Initial followed by infection
• Immune State is results in a Memory Cells.

Viral Immunopathogenesis

• Secondary Viral Challenges prevent symptoms like fever

Viral Mechanisms

• To escape immune sysetm: evade detection, prevent activation