Defenses Against Infection 1. Innate responses (humoral and cellular) 2. Immunity to intracellular pathogens NK cells, control of Th1/Th2 responses 3. Immunity to extracellular pathogens and toxins 4. Immunological Memory 5. Introduction to Evasion of Host Responses

1. Innate responses (humoral and cellular)

Specific for sialic acid Acute-phase response: Early response to infection

Lipoteichoic acid contaminant

‘Endocrine’ effects

Acute-phase response: Early response to infection

Too much of a good thing: Systemic Inflammation (Harmful) (Toxic Shock or Endotoxic Shock) A primary cause of death by infection

Serpin: plasma protease inhibitors (~10% of plasma proteins) Many bacteria produce proteases to establish infection: These are countered by Serpin and  2-macroglobulin Acute-phase response: Early response to infection

 2-macroglobulin  Protease inhibitor in the plasma Acute-phase response: Early response to infection

C-reactive protein Mannose binding lectin Acute-phase response: Early response to infection

2. Immunity to intracellular pathogens

Innate Immunity to Virus Infection: IFN-  Type 1 IFN  produced in response to viral dsRNA Reduced protein synthesis, production of RNAse to degrade viral RNA

NK cells 1. Kill infected or transformed targets 2. Produced IFN-  (activates macrophages) These functions act as a ‘stop-gap’ attempt to control infection while the specific immune response develops.

DO NOT MEMORIZE

intracellular How does the immune system decide to mount a Th1 or Th2 response? intracellular extracellular

Production of IL-12 early in the response promotes Th0 cells to preferentially differentiate into Th1 cells

IL-12 Th1 IL-2 + IFN-  CMI Th2 IL-4 inhibits IL-12 production IL-10 inhibits IFN-  production Early inflammatory response by Dendritic cells and Macrophage (PAMPs) Hypothesis: A Th2 response is generated in the absence of IL-12

3. Immunity to extracellular pathogensand toxins Antibody Function 3.1. Block binding of pathogen or toxin to host cells 3.2. Opsonize for phagocytosis (antigen clearance mediated by Fc receptors on phagocytic cells) 3.3. Activate complement for MAC formation, and generation of C3b and C5a 3.4. Activator of Antibody Dependent Cellular Cytotoxicity (ADCC) 3.5. Degranulate mast cells and eosinophils.

Mast Cells and Eosinophils are Important In Immunity to Worms (very large pathogens) Mast Cells: Production and release of Histamine (vasodilation and smooth muscle contraction) causes flushing action to expel the pathogen and increase eosinophil access to the pathogen. Eosinophils Production of granules that contain Major basic protein and eosinophil cationic protein (and other materials) that are directly toxic to parasites

4. Immunological Memory 4.1 Memory B-cells: Lymphatic circulation and perhaps bone marrow. No surface markers to clearly define memory B-cells. Long-lived and respond rapidly to infection with high affinity ‘switched’ Ig. (Evidence for existence of memory B-cells) 4.2 Memory T-cells: CD45RA to CD45RO expression. Migration in lymphatic circulation, blood, and peripheral tissues including mucosal tissue Memory CD8+ T-cells survive on IL-15. (Evidence for CD8+ memory T-cells is ability to kill targets rapidly and without co-stimulation). Functionally: Faster more robust response that generally protects against damage from infection

Naïve Effector Memory E M

5. Introduction to Evasion of the Host Response Pathogens attempt to resist destruction by many mechanisms including: 5.1 Suppressing/Shifting the Immune Response 5.2 Antigenic Variation 5.3 ‘Hiding’ from the Immune Response

5.1 Suppressing/Shifting the Immune Response Encoding immunosuppressive proteins in the pathogen’s genome that shift responses from Th1 to Th2, or receptors for cytokines to block their activity: viruses express genes for IL-10 Polyclonal activation of lymphocytes by bacterial mitogens (e.g. LPS). Causes partial activation and proliferation of many clones. Without secondary signals resulting in death or poor responses (B-cells make low affinity IgM and don’t switch) Production of bacterial or viral ‘superantigens’ that promote polyclonal T-cell activation; exhaustion of T-cells and cell death; production of inflammatory cytokines by T-cells. Instead of order, the immune system becomes disordered

Superantigens include some bacterial toxins. They induce cytokine production by a large percentage of T-cells (10-20%) that results in an exacerbated inflammatory response. (Toxic Shock Syndrome) TNF and IL-6 are 2 such T-cell derived cytokines Superantigens induce activation of many T lymphocytes

5.2 Antigenic Variation Different ‘strains’ or individuals of a species express antigenically distinct forms of surface molecules: e.g. bacterial serotypes During replication, mutations in genes that encode surface proteins result in new forms of the surface proteins ‘antigenic shift’ or ‘antigen drift’: e. g. viruses such as influenza and HIV Some pathogens carry multiple genes that encode antigenically distinct forms of surface proteins in their genome: e.g. some parasites

5.3 ‘Hiding’ from the Immune System Down regulating MHC expression in infected cells e.g. many viruses Becoming dormant in immunologically privileged sites e.g. viruses such as herpes simplex virus

Defenses Against Infection Many different types of pathogens of various sizes and lifestyles requires a multi-layered system to protect both the extracellular and intracellular environments of the complex human host for a relatively long time.