Host-Path. Interactn & Innate Immunity 5/10/10

Front 1

Key characteristics of bacteria

Back 1

• Prokaryotic cell structure
• Cell wall structures
– Gram positive (purple)
or negative (pink)
• Bacterial virulence factors
– Lipopolysaccharide (LPS)
– Encapsulation
• Toxin production and bacterial diseases
– Exotoxins
• Immune system control of bacterial infections

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Gram negative

Back 2

Cell walls contain lipopolysaccharide (LPS)

- aka: Endotoxin
- a major inflammatory stimulus

- stimulates TLR4

Front 3

Capsules

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Virulence factor commonly exhibited by gram-positive

- Dense outer layer of polysaccharide
- Resistance to Complement Lysis
- Often anti-phagocytic
- Mutants w/o a capsule are avirulent
- Adaptive immune response attaches antibodies to capsule
- ex: Streptococcus pneumoniae

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Virulence factor

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Some component of a pathogen that allows it to evade or resist an innate or adaptive immune response

- capsules
- exotoxins

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Toxin‐producing bacteria

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• Cholera – bacteria stay in gut lumen but produce toxin that causes massive diarrhea

• Tetanus – wound infections by anaerobic bacteria that produces potent neurotoxin

• Diptheria – Corynebacterium diphtheria colonizes pharynx and makes toxin that kills epithelial cells in the throat. Forms pseudomembrane.

• Toxic shock –toxin "superantigens" produced by staphylococcus aureus cause massive stimulation of T cells to secrete cytokines

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Immune system control of bacterial infections

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Antibodies can directly kill some pathogens by:

1. neutralization of exotoxins--> macrophage ingestion
2. complement activation--> lysis
3. opsonization of capsules--> macrophage ingestion

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Life cycle of a virus

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1. Penetration into host cell cytoplasm
- via specific high-affinity ligand-receptor
2. The virus uncoats, separating nucleic acid from protein shell
3. Viral replication in a host cell
4. Self-assembly
5. Released from infected cell to continue cycle

Front 8

Viral Latency

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Ability of a virus to persist in a host indefinitely.

Ex:
1. Herpes simplex- exists in neuronal nucleus as an episomal element (like a plasmid).

2. Hepatitis C- 90% of pts may develop a chronic infection

3. HIV- Retrovirus reverse transcribes into DNA copy that integrates into host chromosome.

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Dimorphic Pathogenic Fungi

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– Candida species normally colonize human skin and are opportunistic pathogens in immunocompromised hosts.

– Cryptococcus neoformans is an opportunistic pathogen that can
cause pneumonia if inhaled by immunocompromised hosts.

– Histoplasma capsulatum is a soil fungus that causes disease when inhaled. It can resist killing by alveolar macrophages until cell‐mediated immunity enhances their killing activity.

– Aspergillus is an opportunistic pathogen that can cause disease
when inhaled by immunocompromised hosts.

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Pathogenic Parasites

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Single cell parasites
– Entamoeba histoytica is an amoeba, which lives it life cycle in the intestine and can invade the intestine and cause ulcers.
– Plasmodium species cause malaria, which follows a complex life cycle with stages expressed in different cell types and involving a mosquito vector

– Trypanosoma species cause African sleeping sickness, syphilis, leprosy.

• Multicellular parasites
– Worms, such as Shistosomas, can cause chronic debilitating infections

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Mechanical barriers to infection
(lo #2)

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- Tight junctions of epithelial cells (skin, gut, lungs, eyes/nose)

- Longitudinal flow of air or fluid (skin, gut)

- Movement of muscus by cilia (lungs)

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Chemical barriers
(lo #2)

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- Fatty acids (skin)
Antibacterial peptides [defensins] (skin, gut, lungs)

- Low pH (gut)
- Enzymes [pepsin] (gut)

-Salivary enzymes [lysozyme] (eyes/nose)

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Microbiological barriers to infection
(lo #2)

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Normal flora
(found on skin & in gut)

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Other barriers
(lo #2)

Back 14

- Cough & gag reflexes
Prevent aspiration into the lungs to prevent pneumonia

- Mechanical methods of removal: intestinal peristalsis, nx urine flow

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Inflammatory Response: Roles
(lo #3)

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1. Deliver additional effector molecules & cells to infection site

2. Induce local blood clotting to produce physical barrier to spreading

3. Promote the repair of damaged tissue (which isn't an immunological process)

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IL-1beta

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Local effects:
-Activates vascular endothelium and lymphocytes.
-Local tissue destruction.
-Increases access of effector cells

Systemic Effects:
-Fever
-Production of IL-6

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TNF-alpha

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Local effects:
-Activates vascular endothelium & increases vascular permeability, leading to increased entry of IgG, complement, and cells to tissues and increased fluid drainage to lymph nodes.

Systemic effects:
-Fever
-Mobilization of metabolites
-Shock

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IL-6

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Local effects:
-Activates lymphocytes
-Increased antibody production

Systemic effects:
-Fever
-Induces acute-phase protein production by hepatocytes

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CXCL8

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Local effects:
Chemotactic factor recruits neutrophils, basophils, & T-cells to site of infection (via specific chemotaxis)

Systemic effects:
n/a

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IL-12

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Local effects:
-Activates NK cells
-Induces differentiation of CD4 T-cells into T<h>1-cells

Systemic effects:
n/a

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How does the innate immune system the presence of pathogens?
(lo#4)

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Use "pattern recognition receptors" (PRRs) to detect "pathogen-associated molecular patterns" (PAMPs).

ex: mannose-binding lectin (MBL) binds w/ high affinity only to mannose and fucose residues in proper orientation.

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TLR receptor family

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"toll-like receptor" family

- A set of PRRs that sense extracellular microbial pathogens and initiate innate immune responses

-Humans have 10 TLR genes; each encodes a different PRR

-TLR recognition of a PAMP is the KEY trigger event in secretion of inflammatory cytokines and chemokines

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How does the innate immune system recognize an intracellular (viral) infection?

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1. RIG-1 & MDA-5 (both PRR sensors) in the cytoplasm detect and bind LONG strands (not nx) of dsRNA.

2. Their binding causes TF's IRF3 & IRF7 to migrate to the nucleus and initiate Type I interferon production.

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Type I Interferons

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Proteins secreted by virally infected cells that can interfere w/ viral replication in fresh cells.

Activates multiple innate immune effectors:
-Induce resistance to viral replication in all cells
-Increase MHC class I expression & antigen presentation in all cells
-Activate dendritic cells & macrophages
-Activate NK cells to kill virus-infected cells

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How do NK cells recognize and eliminate virually infected cells?
(lo #6)

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1. NK cell doesn't kill Nx cells b/c NK inhibitory receptors recognize Nx cell's MHC class I expression.
- This opposes the activating receptors on NK cells

2. Altered cells or those w/o MHC class I expression cannot stimulate the inhibitory receptor. Therefore the NK cell is triggered by signals from its activating receptors.
- This causes NK granule release & induces apoptosis in the abNX cell

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NK cell

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-Develops in bone marrow from lymphoid lineage.
-Nx circulates throughout blood
-Activated by Type I interferons (& others), increasing capacity to kill virally-infected cells by 20-100X