RECOVERY FROM INFECTIONRECOVERY FROM INFECTION

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SHIV VARAN SINGHSHIV VARAN SINGHVBMVBM

M-5547M-5547

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REASON OF INFECTION

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WHO STIMULATE HOST?

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PURPOSE OF RECOVERY

• Prevent progression in recently exposed individuals

• Prevent reactivation in persistently infected individuals

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DIFFERENT TYPE OF STRETEGIESDIFFERENT TYPE OF STRETEGIES

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Pathogen breaches anatomical barriers

• Soluble Proteins in lymph & blood:– C Reactive Protein– Complement

• Phagocytes:– Macrophage-

• 1st cellular defense against an infection!

Phagocytosis Cytokine production

Induces Inflammation & calls in neutrophils

Pathogen persistsAntigen Presentation & Adaptive Immune

Response initiated

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SECOND LINE OF DEFENSE MEDIATED BY RECOGNITION OF BACTERIAL COMPONENTS

• PAMPS- recognized by pattern recognition receptors

• Essential for bacterial growth• PAMPS activate cells via TLRs- expressed on

phagocytes, dendritic cells, epithelial cells.• Recognition of bacteria also occurs in absence of

cells via- – Complement– C- reactive protein– Mannose binding lection– Surfactant protein in lungs

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PhagocytosisPhagocytosis• Ingestion of microorganisms or particulate matter Ingestion of microorganisms or particulate matter

by a cellby a cell1. Attraction (Chemotaxis)

2. Attachment (Opsonization / Coating with Protein)

3. Ingestion

4. Digestion (Lysosomal Enzymes and Oxidizing Agents)

5. Expulsion

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Mechanism of PhagocytosisMechanism of Phagocytosis

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The interaction of M with pathogens

What PRProteins & receptors are on the

M?• M Mannose Receptor:

–C-type Lectin (PRP)

–Binds mannose, N acetylglucosamine, & fucose residues on pathogen surface molecules.

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• Scavenger Receptors:– Group of @ least 6

molecular forms.– Recognize lipoproteins on

Gm + & Gm – bacteria. – Involved in elimination of

old & apoptotic cells.

• Glucan receptor- – Dectin-1: C-type lectin (PRP)

– Binds -glucans (LPS)

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Killing mechanism of phagocyteKilling mechanism of phagocyte

• Oxygen dependent• Oxygen independent• TNF-α & IFN-γ causes

production of NO synthase

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• 2. Oxygen dependent killing mechanisms:

– A) Enzymes to make Reactive oxygen radicals (ROIs):• NADPH oxidase- phagosomal membrane–Multicomplex protein.– Reduction of O2 superoxide anion (O2-):

• SOD: converts superoxide to H2O2

• Myeloperoxidase- lysosomal protein– Produces Hypochlorous acid (OCl-) & Hydroxyl Radicals.

Oxygen-Independent Killing mechanisms:

• . Oxygen-Independent Killing mechanisms:

– Hydrolytic enzymes:

• Lysozyme

• Proteases

• RNases & DNases.

– Defensins:

• cationic peptides (cysteine); 29-35 AA.

– Competitors-

• Lactoferrin- compete cells for iron

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B) Reactive Nitrogen Intermediates (RNIs). – nitric oxide synthetase (NOS): • NO can be easily converted to peroxynitrite anion &

nitrogen dioxide.

NADPH NADP

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LYMPHOCYTE- INDEPENDENT BACTERIAL RECOGNITION PATHWAY• Alternate complement pathway

– Bacteria with outer lipid bi-layer- susceptible to lytic complex (C5b-9)– C5a- anaphlatoxins-

– neutrophil recruitment – mast cell degranulation- histamine, Opsonins- C3 derivatives-

phagocytosis• Pro-inflammatory cytokines increase adhesive properties of

vascular endothelium– Macrophages- TNF & IL-1

• Macophages- IL-12, IL-18 - NK cells- IFN-γ- activates macrophages (first day of infection)

• SCID mice (defect in lymphocyte maturation) can resist Listeria monocytogenes infection

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Natural killer (NK) cellsNatural killer (NK) cells

• Natural killer (NK) cells use the same effectors to kill virus-infected cells and tumors.

• Do not require stimulation, nor do they exhibit memory.

• NK cells respond in the absence of MHC proteins.

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NK T cells

• Thymus derived cells

• In between innate and adaptive immunity

• Phenotypically and functionally similar to NK cells

• It express TCR

• Marker NK1.1, which recognize an MHC-associated CD1 receptor expressed on APC

• Cytokine production, IL-4 and INF- ϒ (Immunoregulatory role) & kill target cells

• Rapidly produce large amounts of different cytokines upon activation.

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Specific Immune Strategies

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Endogenous Pathway Exogenous Pathway

Antibody mediated strategy

• Antibody plays a crucial role in dealing with bacterial toxins– Ab neutralizes diphtheria toxin- blocks attachment of the toxin to the

target cells– Ab blocks locally acting toxins or extracellular matrix degrading

enzymes which act as spreading factors• Interfere with motility of flagella• IgA- immune evasion & immune exclusion mechanism- mucosal

immunity• Ab to bacterial cell surface block functional requirements of the

organism- intake of nutrients or iron-chelating compounds• Immunity to non-toxigenic bacteria- more efficient targeting of

complement• Bacteria that resist alternative complement pathway are damaged

by compliment or coated with C3 products- enhance phagocytosis

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Antigen contact antigen-specific B cell that processes the antigen and presents it to an antigen-specific TH2 cell. The

activated TH2 cell then signals

the antigen-specific B cell to produce antibody.

Activated B cells live for years as memory cells and can rapidly produce large quantities (high titers) of antibodies upon re-exposure to antigen.

Cont…Cont…

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T- lymphocytesT- lymphocytes

The antibody or TCR does not interact with the antigenic macromolecule as a whole but only against a distinct portion of the molecule called an antigenic determinant or epitope.

T cells recognize antigens presented by antigen-presenting cells (APCs) or by pathogen-infected cells.

At the molecular level, TCRs bind peptide antigens presented by major histocompatibility complex (MHC) proteins. Class I MHC proteins are found on the surfaces of all nucleated cells.

Class II MHC proteins are found only on the surface of B lymphocytes, macrophages, and dendritic cells, all of which are APCs.

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molecular interactions stimulate T cells to kill antigen-bearing cells or to molecular interactions stimulate T cells to kill antigen-bearing cells or to produce cell-stimulating proteins known as cytokines.produce cell-stimulating proteins known as cytokines.

MHC- I MHC-II

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T-Helper CellsT-Helper Cells

• TH1 and TH2 cells play pivotal roles in CMI & and antibody-mediated immune responses.

• TH1 inflammatory and TH2 helper cells each stimulate effector cells through the action of cytokines.

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T-Cytotoxic CellsT-Cytotoxic Cells

T-cytotoxic (TC) cells recognize antigens on virus-infected host cells, intracellular bacteria and tumor cells through antigen-specific TCRs. Antigen-specific recognition triggers killing via perforin and granzymes.

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CONT…CONT…

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CONCLUSIONSCONCLUSIONS• Non specific barrier viz; skin, mucus membrane

etc.• Secretion of body viz; lysozyme, Hcl,

antimicrobial substance etc.• Normal flora of body.

• Fever, inflammation etc.

• CMI and HMI

• Complement system

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