Lesson 10: Innate Immunity/ Nonspecific Defenses of the Host March 24, 2015.

Lesson 10: Innate Immunity/ Nonspecific Defenses of the Host

March 24, 2015

Overview

• Our bodies are constantly being attacked by microbes– Susceptible—the inability to ward off disease– Immunity—ability to fight off a disease

• Immune system—is a set of biological structures and systems that protect an organisms from invading pathogens– Innate Immunity– Adaptive Immunity

• Innate Immunity—refers to defenses that are present at birth– The body’s first line of defense against invading

microorganisms– Always present to provide a rapid response to

protect against disease– No memory response present

• Multiple infections with same organism would produce similar response

• Components of Innate Immunity– First line of defense

• Skin and mucous membranes– Lacrimal glands (eye), saliva, urine, vaginal secretions– Mucous is secreted by goblet cells in epithelial lining

– Second line of defense• Natural killer cells• Phagocytes• Inflammation • Fever• Antimicrobial substances

• Serves as the body’s early-warning system– Designed to prevent microbes from gaining access

into the body– The microbes that slip past the skin and mucous

membranes usually are eliminated by the innate immune system

• Also referred to as “non-specific immunity”

• Responses of the innate system are activated by protein receptors (Toll-like receptors) on the plasma membrane of defensive cells

• Toll-like receptors (TLRs) recognize various components found on/in pathogens (pathogen-associated molecular patterns)

• Examples of PAMPs– Lipopolysaccharide (LPS)– Peptidoglycan – Flagella– DNA

• Each TLR can recognize a specific PAMP– Multiple TLRs can be used to bind one PAMP– 13 TLRs have been identified. Function of two are unknown

• Binding of TLR to PAMP induces a chemical response– Cytokines—proteins released by the cell to signal an

infection has taken place– Cytokines regulate the intensity and duration of an immune

response– One role of cytokines is to recruit other immune cells to the

site of the infection

• Cytokines function in both Innate and Adaptive immunity– Cytokines recruits macrophages and dendritic cells

to the site of the infection

– Cytokines activate T-cells and B-cells involved in adaptive immunity. (stimulates antibody production)

• Adaptive immunity—the portion of the immune system that “remembers” an attacking pathogen– Activated when innate immunity fails to stop an

invading microbe– Slower activation than innate immunity but

contains a memory component– Specific immunity “Particular response for a

specific microbe”

• Components of adaptive immunity– T-cells (T-lymphocytes)– B-cells (B-lymphocytes)

• Lymphocytes are a type of white blood cell

First line of defense

• Intact skin• Mucous membranes and their secretions• Normal microbiota

Second line of defense Third line of defense

• Specialized lymphocytes: T cells and B cells• Antibodies

• Phagocytes, such as neutrophils, eosinophils, dendritic cells, and macrophages• Inflammation• Fever• Antimicrobial substances

Figure 16.1 An overview of the body’s defenses.

Innate Immunity

• The first line of defense against an invading pathogen is the skin and mucous membranes– Physical factors—provide a physical barrier

• Skin• Mucous membranes

– Chemical factors—secrete chemicals that inhibit growth or eradicates the bacteria

Physical Factors

• Skin– Largest organ in the body– Dermis—skin’s inner,

thicker portion. Composed of connective tissue

– Epidermis—skin’s outer, thinner layer. Direct contact with the external environment

• Keratin—protective layer of protein

epidermis w/ keratin

epidermis

dermis

• Anti-microbial properties of the skin– Shedding of the top layer of epidermis aids in the

removal of microbes (sloughing)– Dryness of the skin prevents microbial colonization

• Populations in humid climates have a greater incidence of skin infections

• Athletes Foot Fungus (Trichophyton spp)

– Compactness of the cells prevents pathogen passage (tight junctions)

– pH of skin is between 3-5

• Mucous membranes– Consists of epithelial

layer and connective tissue

– Line the gastrintestinal, respiratory, and genitourinary tracts

– Goblet cells secretes mucous (slightly viscous glycoprotein)

• Prevents colonization

Connective Tissue

Epithelial Layer

Mucus

Other Physical Barriers

• Lacrimal apparatus (tear ducts) washes microbes and other particulates from the eyeball

• Saliva dilutes the numbers of microbes and washes them from the teeth and mucous membranes of the mouth

• Hair aids in filtering the inhaled air by trapping microbes, dust, and pollutants

Other Physical Barriers

• Cilia are hair-like structures on cells that help propel particulates out of the lower respiratory tract (ciliary escalator)– Toxins in cigarette smoke impair cilia function

B. pertussis

Cilia

Figure 24.7 Ciliated cells of the respiratory system infected with Bordetella pertussis.

© 2013 Pearson Education, Inc.

Other Physical Barriers

• Cilia are hair-like structures on cells that help propel particulates out of the lower respiratory tract (ciliary escalator)– Toxins in cigarette smoke impair cilia function

• Epiglottis is a small flap of cartilage in the larynx

• Earwax traps microbes in the external ear

Other Physical Barriers

• Urine/vaginal secretions functions by mechanically cleaning the urethra and vagina, respectively

• Peristalsis, defecation, vomiting, diarrhea all act to remove microbes and toxins from the body– Contraction of gastrointestinal muscles is an effort

of the body to remove toxins (stomach pains)

Chemical Factors

• Sebaceous (oil) glands secretes sebum that forms a protective film over the skin surface– Sebum contains unsaturated fatty acids that prevents the

growth of certain pathogens– Contributes to acidic pH (3-5) of the skin

• Perspiration (sweat) eliminates certain wastes and microbes from the body– Also contains lysozyme—enzyme that breaks down the cell

wall of Gram (+) bacteria and some Gram (-) bacteria• Found in tears, saliva, nasal secretions, tissue fluids, & urine• PEPTIDOGLYCAN!!!!

• Earwax is a mixture of secretions rich in fatty acids (lowers pH)– Sebaceous glands– Sweat glands

• Saliva contains lysozyme, urea, and uric acid that inhibit microbial growth– Immunoglobin A (antibody) that prevents

microbial attachment to cells

• Gastric juice – Produced by stomach glands. – Very acidic (pH 1.2-3.0)– Destroys microbes and their toxins

• Vaginal Secretions – Contains glycogen that is digested by Lactobacillus

acidophilus, resulting in lactic acid (pH 3-5)• Urine

– Contains lysozyme that lowers pH thus inhibiting microbial growth

Normal Microbiota

• The normal flora also acts as a first line of defense against invading pathogens– Microbial antagonism

• Changes in pH– Prevents Candida albicans growth in the vagina

• Oxygen availability• Production of bacteriocins that inhibit growth of

pathogens– E. coli production of bacteriocins prevent Shigella and

Salmonella growth

• Competition for nutrients

• Probiotics—live microbial cultures applied to or ingested to exert a beneficial effect– Prebiotics (chemicals that selectively promote

growth of beneficial bacteria)– Studies have shown that the introduction of

certain lactic acid bacteria can prevent the growth by Salmonella enterica

Innate Immunity: Nonspecific Defenses of the Host

Second Line of Defense

• If a microbe escapes the first line of defense, the body begins mounting a second wave of defense– Production of phagocytes– Inflammation– Fever– Antimicrobial substances

Formed Elements in Blood

• Blood consists of plasma (fluid) and formed elements (cells and cell fragments)

• Cells of the blood– Erythrocytes– Leukocytes (white blood cells)

• Granulocytes• Agranulocytes

• During an infection, the number of leukocytes can increase (leukocytosis) or decrease (leukopenia)

Insert Table 16.1If possible, break into multiple slides

Table 16.1 Formed Elements in Blood (Part 1 of 2)

Insert Table 16.1If possible, break into multiple slides

Table 16.1 Formed Elements in Blood (Part 2 of 2)

• Percentage of each type of white cell in a sample of 100 white blood cells

Neutrophils 60–70%

Basophils 0.5–1%

Eosinophils 2–4%

Monocytes 3–8%

Lymphocytes (NK cells, T and B cells) 20–25%

Differential White Cell Count

Lymphatic System

• Is part of the circulatory system that functions by carrying a clear liquid (lymph) towards the heart

• Transports leukocytes and antigen-presenting cells to and from lymph nodes

• Lymph nodes are organized collection of lymphoid tissue through which lymph passes before circulating back into the blood

• Lymph nodes are primarily found in the neck, chest, armpit, pelvis, groin, and intestines

Rightlymphaticduct

Rightsubclavian vein

Leftsubclavianvein

Thoracic(leftlymphatic)duct

Tonsil

Thymus

Lymphatic vessel

Large intestine

Redbone marrow

Heart

Thoracic ductSpleen

Small intestine

Peyer’s patch

Lymph node

(a) Components of lymphatic system

Figure 16.5a The lymphatic system.

Lymphatic capillary

Lymph

Interstitialfluid (between cells)

Blood

Arteriole

Blood capillary

Blood

Tissue cell

Venule

Relationship of lymphatic capillaries to tissue cells and blood capillaries

Figure 16.5b-c The lymphatic system.

Lymph

Tissue cell

Lymphatic capillary

Interstitial fluid

One-way opening

Details of a lymphatic capillary

Phagocytosis

• Ingestion of microbes or particles by a cell, performed by phagocytes– Phago: from Greek, meaning eat– Cyte: from Greek, meaning cell

• Neutrophils and eosinophils function in phagocytosis

• Monocytes mature into macrophages– Fixed macrophages– Wandering (circulating) macrophages

Pseudopods

Bacterium

Macrophage

Figure 16.6 A macrophage engulfing rod-shaped bacteria.

Mechanism of Phagocytosis

1. Chemotaxis—chemical attraction of phagocytes to microbes

2. Adherence—attachment of the phagocyte’s plasma membrane to the microbe or other foreign particle

– Action is enhanced with opsonins

3. Ingestion—uptake of microbe into the cell4. Digestion—breakdown of microbe via

digestive enzymes in lysosomes

Pseudopods

Phagocyte

Cytoplasm

Microbeor otherparticle

Details ofadherence PAMP (peptidoglycan

in cell wall)

TLR(Toll-like receptor)

Lysosome

Digestiveenzymes

Indigestiblematerial

Plasma membrane

Partiallydigestedmicrobe

CHEMOTAXISandADHERENCEof phagocyte tomicrobe

1INGESTIONof microbe by phagocyte

2

Formation of phagosome(phagocytic vesicle)

3

Fusion of phagosomewith a lysosometo form a phagolysosome

4

DIGESTIONof ingestedmicrobes byenzymes in thephagolysosome

5

Formation ofthe residual bodycontainingindigestiblematerial

6

DISCHARGE ofwaste materials

7

A phagocytic macrophage uses a pseudopod to engulf

nearby bacteria.

Figure 16.7 The Phases of Phagocytosis.

Pg. 461 of textbook

Inhibit adherence: M protein, capsules

Streptococcus pyogenes, S. pneumoniae

Kill phagocytes: Leukocidins Staphylococcus aureus

Lyse phagocytes: Membrane attack complex

Listeria monocytogenes

Escape phagosome Shigella, Rickettsia

Prevent phagosome–lysosome fusion

HIV, Mycobacterium tuberculosis

Survive in phagolysosome Coxiella burnettii

Microbial Evasion of Phagocytosis

Inflammation

• Damage to the body’s tissues triggers a local defensive response called inflammation– Not only generated by microbes

• Inflammation is characterized by four signs/symptoms– Redness– Swelling (edema)– Pain– Heat

• Binding of microbial structures stimulate the Toll-like receptors of macrophages and they begin producing TNF-alpha

• Activation of acute-phase proteins (complement, cytokine, and kinins)

• Vasodilation (histamine, kinins, prostaglandins, and leukotrienes)

Histamine Vasodilation, increased permeability of blood vessels

Kinins Vasodilation, increased permeability of blood vessels

Prostaglandins Intensify histamine and kinin effect

Leukotrienes Increased permeability of blood vessels, phagocytic attachment

Chemicals Released by Damaged Cells

Bacteria enteringon knife

Epidermis

Dermis

Subcutaneoustissue

(a) Tissue damage

Bacteria

Blood vessel

Nerve

Figure 16.8a-b The process of inflammation.

Chemicals such as histamine, kinins, prostaglandins, leukotrienes, and cytokines (represented as bluedots) are released bydamaged cells.

(b) Vasodilation and increasedpermeability of blood vessels

Blood clot forms.

Abscess starts to form(orange area).

1

2

3

Insert Fig 16.8c

Margination—phagocytes stickto endothelium.

Diapedesis—phagocytes squeeze between endothelial cells.

Phagocytosis ofinvading bacteria occurs.

(c) Phagocyte migrationand phagocytosis

Macrophage

Bacterium Neutrophil

Redbloodcell

Blood vesselendothelium

Monocyte

6

5

4

Figure 16.8c The process of inflammation.

Fever

• Abnormally high body temperature• Hypothalamus is normally set at 37°C• Gram-negative endotoxins (LPS) cause

phagocytes to release interleukin-1 (IL-1)• Hypothalamus releases prostaglandins that reset

the hypothalamus to a high temperature• Body increases rate of metabolism, chills begin

and shivering occurs, which raise temperature• Vasodilation and sweating: body temperature

falls (crisis)

The Complement System

• 30+ proteins produced by the liver and are located in blood serum throughout the body– Serum proteins are activated in a cascade

• Activated by– Antigen–antibody reaction (Classical)– Complement C3 binds the factors B, D, P on a

pathogen (Alternative)– Liver produces Lectins that bind to carbohydrates

Effects of Complement Activation• Opsonization, or immune adherence: enhanced

phagocytosis– C3a and C5a

• Membrane attack complex: cytolysis– C5b, C6, C7, C8, C9 (multiple copies)

• Attract phagocytes– C5a (chemoattractant)

Insert Fig 16.9

Inactivated C3 splits into activatedC3a and C3b.

C3b binds to microbe, resultingin opsonization.

C3bproteins

opsonizationEnhancement of phagocytosisby coating with C3b

C5b, C6, C7, and C8 bindtogether sequentially andinsert into the microbialplasma membrane, wherethey function as a receptorto attract a C9 fragment;additional C9 fragments areadded to form a channel.Together, C5b through C8and the multiple C9fragments form themembrane attack complex,resulting in cytolysis.

C3

C3b C3a

C5

C5b C5a

C6

C7

C8

C9

Mast cell

C3a receptor

Microbialplasmamembrane

Channel

C9

C6

C7C8

C5b

C5aC5a receptor

Histamine

inflammationIncrease of blood vesselpermeability and chemotacticattraction of phagocytes

C9C8

C7C6

C5b

CytolysisFormation of membraneattack complex (MAC)

C3a

C3a and C5a causemast cells to releasehistamine, resultingin inflammation;C5a also attractsphagocytes.

1

2

3

4

5C3b also splits C5 into C5a and C5b

Bursting of microbe due to inflow of extracellular fluid throughtransmembrane channel formed by membrane attack complex

cytolysis

Figure 16.9 Outcomes of Complement Activation.

© 2013 Pearson Education, Inc.

Pg. 468 oftextbook

Insert Fig 16.10

Figure 16.10 Cytolysis caused by complement.

Insert Fig 16.11

C5a receptorC5a

Histamine-containinggranule

Histamine-releasingmast cell

C3a receptor

Histamine

C3a

Neutrophil

Phagocytes

C5a Macrophage

Figure 16.11 Inflammation stimulated by complement.

Insert Fig 16.12

C1 is activatedby binding toantigen–antibodycomplexes.

Activated C1 splitsC2 into C2a andC2b, and C4 intoC4a and C4b.

C2a and C4b combine and activate C3, splittingit into C3a and C3b (see also Figure 16.9).

C3

Opsonization Inflammation

Cytolysis

C3b C3a

C2 C4

C1

Microbe

Antibody

C4aC2bC2a C4b

Antigen

Figure 16.12 Classical pathway of complement activation.

Insert Fig 16.13

Microbe

Lipid-carbohydratecomplex

Opsonization

B D P

C3b C3a

Inflammation

C3

Cytolysis

B B factor D D factor P P factorKey:

C3 combines withfactors B, D, and Pon the surface ofa microbe.

This causes C3 tosplit into fragmentsC3a and C3b.

Figure 16.13 Alternative pathway of complement activation.

C3

Opsonization Inflammation

Cytolysis

C3b C3a

C2 C4

C4aC2b C2a C4b

MicrobeCarbohydratecontainingmannose

Lectin

Bound lectinsplits C2 intoC2b and C2aand C4 intoC4b and C4a.

Lectin binds toan invading cell.

C2a and C4b combineand activate C3 (see also Figure 16.9).

Figure 16.14 The lectin pathway of complement activation.

Some Bacteria Evade Complement

• Capsules prevent C activation– Disallows Ab from binding to bacteria thus preventing

C1 binding• Surface lipid–carbohydrate complexes prevent

formation of membrane attack complex (MAC)– Modification of sugars on the bacterial membrane

abrogates C5b-C9 from binding to surface• Neisseria gonorrhoeae

• Enzymatic digestion of C5a– Gram positive cocci (Streptococcus pyogenes)

Interferons (IFNs)

• Interferons—class of similar anti-viral proteins produced by certain animal cells and function to abrogate viral multiplication– Host cell specific and not viral specific

• IFN- and IFN-: produced by virally-infected cells and causes neighboring cells to produce anti-viral proteins that inhibit viral replication– Oligoadenylate synthetase—degrades viral mRNA– Protein kinase—inhibits protein synthesis

• IFN-: produced by lymphocytes and causes neutrophils and macrophages to phagocytize bacteria– Produce iNOS (nitric oxide) that inhibits ATP production

Insert Fig 16.15

Viral RNA froman infecting virusenters the cell.

The infecting virusalso induces thehost cell to produceinterferon mRNA(IFN-mRNA), whichis translated intoalpha and beta interferons.

Viral RNA

Infectingvirus Viral RNA

Transcription

Nucleus

Translation

IFN-mRNA

Alphaand betainterferons

Virus-infected host cell

Translation

Transcription

Neighboring host cell

AVPs degradeviral mRNA andinhibit proteinsynthesis—andthus interferewith viralreplication.

Antiviralproteins(AVPs)

New viruses released by the virus-infected host cell infect neighboring host cells.

The infecting virusreplicates intonew viruses.

Interferons released by thevirus-infected host cell bindto plasma membrane ornuclear membrane receptors on uninfected neighboring host cells, inducing them tosynthesize antiviral proteins(AVPs). These includeoligoadenylate synthetaseand protein kinase.

12

3

4

5

6

Figure 16.15 Antiviral action of alpha and beta interferons (IFNs).Pg. 471 of textbook

Innate Immunity

• Iron-binding proteins– Bind free-iron in

serum– Siderophores—

proteins that microbes secrete to bind iron

• Antimicrobial peptides– Chain of 15-20 amino

acids– Lyse bacterial cells– Production triggered by

protein and sugar molecules on surface of microbes

KNOW TABLE ON PAGE 474