Innate Host Defense Mechanism.ppt

Our bodies are constantly under attack by an army of microorganisms, toxins, allergens and other substances that are recognized as foreign (non-self).

The ways in which the body protects itself from pathogens can be thought of as an army consisting of three lines of defense.

1. Host Defense Mechanism
Hawler Medical University
College of Health Sciences
Medical Microbiology Dept.
Dr. Amer Ali Khaleel
(Ph.D. Medical Immunology)
Lecture 4 & 5
2
nd
stage
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2. Introduction:
•Ourbodiesareconstantlyunderattackbyanarmyof
microorganisms,toxins,allergensandothersubstancesthatare
recognizedasforeign(non-self).
•Thewaysinwhichthebodyprotectsitselffrompathogenscanbe
thoughtofasanarmyconsistingofthreelinesofdefense.
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3. 3

4. 4

5. 5

6. Introduction:
•An immune response is a physiological process coordinated by the
immune system to eliminate foreign substances (antigens).
•Our immune system includes two key branches: innateand adaptive
immunity.
•The three common features of both branches are that they
(1) Recognize diverse pathogens,
(2) Eliminate identified invaders, and
(3) Discriminate between self and foreign antigens.
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7. No. Features Innate Immunity Tools
1Speed of action Rapidly (Minutes to Hours)
2Development of memoryNo
3Specificity of recognitionBroad
4Self/non-self-discriminationPerfect
5Activity Always present
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Soluble components
(factors) of blood or tissue
fluid
Many antimicrobial peptides (AMP), acids,
lysozyme, complement serum protein & other
mediators (like cytokines)
7Major cell types
Phagocytes (macrophages, neutrophil), dendritic cell
(DC), natural killer cells (NK), other granular
leukocytes, epithelial and endothelial cells
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Important Features of Non Specific / Innate / Natural Immunity

8. No. Features Innate Immunity Tools
8Major Histocompatibility
Complex
No MHC restricted
9Receptor Have receptors called Pattern Recognition Receptors
(PRR)
10Exposure to the same
pathogen
No increase in response upon repeated exposure to
the same pathogen
11Response Uptake and clearance, danger signaling
12Target Groups of pathogens
13Anatomic and chemicals Skin, mucosa, chemicals & pH
14APCs Not require
15Coordinator None
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9. Introduction to first-line defenses
(external defense)
First-line defenses aim to prevent pathogen entry
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For convenience, The traditionally subcategorize these
defenses as physical, chemical, and microbiota
barriers.

10. 1-Physical (Anatomical) barriers:
Physical barriers prevent the entry of organism into the body and consist of the
following:
1-Intact skin: Covered by outer tough layer called horny layer or stratum corneum and
consisting of dead, fully, keratinized cells successfully prevents the entry of pathogens.
But when the skin is damaged as in burns, traumatic injury or surgery, infectious can be
a serious problem, skin is one of our most important physical barriers.
2-Intact mucosal lining of different organs acts as a protective barrier to block the
adherence of bacteria to epithelial cells.
3-Nasal hair: Don’t allow dust particles and microorganism enter the respiratory tracts.
4-Earwax is another sticky substance that traps microbes and makes tissue invasion
more difficult.
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11. 2-Chemical barriers:
There are a number of chemical barriers that control microbial growth:
1-Fatty acids of skin, acid pH of sweat and sebaceous secretions inhibit growth of
microorganisms, due to their bactericidal effect.
2-Lysozymepresent in tears, nasal secretions and saliva and in almost secretion except
in cerebrospinal fluid, degrades peptidoglycan an essential element presents in bacterial
cell wall (especially Gram-positive bacteria).
3-Spermine and zinc in the semen are bactericidal effect.
4-Lactoperoxidasein milk has bactericidal action.
5-Gastric juice is produced by the glands of the stomach.
6-Vaginalsecretions play a role in antibacterial activity.
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12. •The normal microbiota is the group
of microorganisms routinely found
growing on the body of healthy
individuals. The community is also
called the microbiome(the term is
also used to refer to the total genetic
information of the community).
•Microbes that typically inhabit body
sites for extended periods are resident
microbiota, whereas temporary
occupants are transient microbiota.
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3-Normal Microbiota (Flora):
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13. •Thenormalmicrobiotapreventspathogensfromcolonizingthehostby
competingwiththemfornutrients(competitiveexclusion),byproducing
substancesthatareharmfultothepathogens,andbyalteringconditionsthat
affectthesurvivalofthepathogens,suchaspHandoxygenavailability.
•Thepresenceofnormalmicrobiotainthevagina,forexample,alterspH,
thuspreventingoverpopulationbyCandidaalbicans,apathogenicyeastthat
causesvaginitis.
•Inthelargeintestine,E.colibacteriaproducebacteriocinsthatinhibitthe
growthofSalmonellaandShigella.
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14. Introduction to second-line defenses
(Internal defense)
Second-line defenses kick in when first-line defenses
are breached.
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15. •Foritssecondlineofdefense,thebodyusesanenormousnumberof
cellsandchemicals.
•Thesedefensesrelyonthedestructivepowersofcellscalled
phagocytesandnaturalkillercells,ontheinflammatoryresponse(isa
nonspecificresponsethatistriggeredwheneverbodytissuesare
injured),andonavarietyofchemicalsubstancesthatkillpathogens
andhelprepairtissue.Feverisanothernonspecificprotectiveresponse.
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16. •Fever (pyrexia) is an abnormally high
systemic body temperature.
•Fever, or abnormally high body
temperature, is a systemic response to
invading microorganisms which is
different from the “local heat” that
characterizes inflammation.
Fever :
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17. •Infectious agents trigger fevers, fever-inducing agents are called
pyrogens(pyro = fire/heat; gen = genesis/creation).
•Many bacterial toxins act as pyrogens, particularly endotoxin
(lipopolysaccharide) found in the outer membrane of Gram-negative
bacteria.
•Pyrogens trigger the release of cytokines, especially interleukin 1,
tumor necrosis factor, and interferon alpha, which signal the
hypothalamusof the brain to raise the body’s baseline temperature
from 37°C to a higher temperature.
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18. •Although high fevers are dangerous because excess heat “scrambles”
(destroys protein structure) enzymes and other body proteins,
rendering them nonfunctional, mild or moderate fever seems to
benefit the body.
•Bacteria require large amounts of iron and zinc to multiply, but
during a fever the liver and spleen gather up these nutrients, making
them less available. Fever also increases the metabolic rate of tissue
cells in general, speeding up repair processes.
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19. 19

20. Benefits of Fever
1.Inhibits growth of some M.O.
2.Enhances the effects of interferons.
3.May enhance the performance of
phagocytes, cells of specific
immunity, and the process of tissue
repair.
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21. •Inflammationisaninnateimmuneresponsethattendstodevelop
whenourtissuesaredamaged,eitherfromphysicalfactorsliketraumaor
burns,orfrominfectiousagents.
•Althoughaphysicalinjuryoftenintroducesaninfectiousagent,such
aswhenaskincutallowsapathogentogainentry,theinjurycouldalso
beaseptic,meaningitdoesn’tintroduceaninfectiousagent.
Inflammation:
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22. What's the difference
between infection and
inflammation?
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23. It has two types:
A)Acuteinflammation:
Developsquicklyandisshortlived,Isusuallybeneficial,Importantin
thesecondlineofdefense,dilationandincreasedpermeabilityofthe
bloodvessels,migrationofphagocytes,tissuerepair.
B)Chronicinflammation:
Developsslowlyandlastsalongtime,Cancausedamagetotissues.
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24. 1.The offending agent, which is located in extravascular tissues, is
recognized by host cells and molecules.
2.Leukocytes and plasma proteins are recruited from the circulation to
the site where the offending agent is located.
3.The leukocytes and proteins are activated and work together to
destroy and eliminate the offending substance.
4.The reaction is controlled and terminated.
5.The damaged tissue is repaired.
The typical inflammatory reaction develops through a series of
sequential steps:
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25. This figure just for preview
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26. The Cardinal Signs of Inflammation
scab
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28. Cellularsecond-line Defenses:
Althoughthephysicaldefensebarriersdoanexcellentjobofkeepingmicrobesoutof
ourbodies,weconstantlysufferminorbreachesofthephysicaldefensebarriers.A
papercut,thecrackingofdryskin,orevenbrushingourteethmaytemporarily
breachthephysicaldefensesandallowsomemicrobestoenterthebloodor
connectivetissue.
However,wesurvivethesedailyattacksbecauseever-presentcellulardefensescan
killinvadingmicrobesorremovethemfromthebloodortissues.
Still,ifmicroorganismsenterbloodthroughcutsintheskin,cellulardefense
mechanismscomeintoplay.
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**

29. Phagocytosis:
•Phagocytesarecellsthatliterallyeatorengulfothermaterials.They
patrol,orcirculatethroughthebody,destroyingdeadcellsandcellular
debristhatmustberemovedconstantlyfromthebodyascellsdieand
arereplaced.Phagocytesalsoguardtheskinandmucousmembranes
againstinvasionbymicroorganisms.Beingpresentinmanytissues,
thesecellsfirstattackmicrobesandotherforeignmaterialatportalsof
entry,suchaswoundsinskinormucousmembranes.
•Ifsomemicrobesescapedestructionattheportalofentryandenter
deepertissues,phagocytescirculatinginbloodorlymphmounta
secondattackonthem.
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30. Several types of cells in the immune system engulf microorganisms
viaphagocytosis, Which are mainly; Neutrophils, Macrophages,
Dendritic Cells &B Lymphocytes.
The Process of Phagocytosis:
•Ifaninfectionoccurs,phagocyticcellsusethisfour-stepprocessto
destroytheinvadingmicroorganisms.
(1)Recognition,
(2)Adherence,
(3)Engulfment,and
(4)Intracellularkilling.
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31. 31
Figure: Phases of Phagocytosis

32. Phagocytes: Neutrophils vs Macrophages:
*Neutrophilsdieandlyseafterextendedphagocytosis.Thismakesupthe
characteristicpropertiesofpus.
*Unliketheneutrophil,macrophagecanpresenttheantigenicfragmentstotheTcells
inthecontextofMHCclassIImoleculesafterengulfingthebacterialcells.
*Macrophagesdigesteddebrisandallowinsertionofmicrobialantigeniccomponents
intotheplasmamembraneforpresentationtolymphocytesintheimmunological
response.
*Macrophagescanlivelongerthanneutrophils.
*Sincemacrophagesarelargerthanneutrophils,theycanphagocytegreaternumberof
invaderpathogensthanneutrophils.
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33. •Mostmacrophagescanliveforseveralmonthsandcankillhundredsofdifferent
bacteriabeforetheydie.Thatdestroynotonlymicroorganismsbutalsolarger
particles,suchasdebrisleftfromneutrophilsthathavediedafteringestingbacteria.
Althoughmacrophagestakelongerthanneutrophilstoreachaninfectionsite,they
arriveinlargernumbers.
•Macrophagescanbefixedorwandering.
•Fixedmacrophagesremainstationaryintissuesandaregivendifferentnames,
dependingonthetissueinwhichtheyreside.
•Wanderingmacrophages,liketheneutrophils,circulateintheblood,movinginto
tissueswhenmicrobesandotherforeignmaterialarepresent.
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Phagocytes: Neutrophils vs Macrophages:

34. Intracellular Killing:
•Two separate systems of destructive chemicals await the microbes in
the phagolysosome.
•The oxygen-dependent system (known as the respiratory burst, or
oxidative burst) involves several substances.
•The oxygen-dependentmechanisms of intracellular digestion are
activated as a result of this process.
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35. ●NADPH oxidase reduces oxygen (O
2) to superoxide anion (.O
2-)
, which generates hydroxyl radicals (.OH.) and hydrogen peroxide
(H
2O
2), which are microbicidal.
●Myeloperoxidasein the lysosomes acts on hydrogen peroxide (H
2O
2)
and chloride ions (Cl
-
) to produce hypochlorite (ClO
−
) , which is
microbicidal.
Reactive oxygen species(ROS) ,Nicotinamide adenine dinucleotide phosphate (NADPH),nitric oxide(NO)
Arginin=a.aCitrulline=a.a
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36. •The lysosomal contents of phagocytes contain oxygen-independentdegradative
materials:
●Lysozyme digests bacterial cell walls by cleaving peptidoglycan.
●Defensins form channels in bacterial cell membranes.
●Lactoferrin chelates iron.
●Hydrolytic enzymes.
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37. •A number of defense molecules mediate innate immune responses
which includes:
Antimicrobial Proteins.
Interferons.
Iron-binding proteins.
Acute Phase Response.
Complements systems. (covered in next year)
Molecularsecond-line Defenses:
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38. •Antimicrobial peptides (AMPs) are proteins that act as chemical
barriers by destroying a wide spectrum of viruses, parasites, bacteria,
and fungi.
•Thousands of different AMPs exist and they have diverse modes of
action.
•The most important of these are complement and interferon.
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Antimicrobial peptides (AMPs):

39. 39

40. •A collection of signaling molecules called interferons give the alarm when
pathogens or tumor cells are detected. They are especially well known for
antiviral effects, and derive their name from their ability to “interfere” with viral
replication.
•Many classes of interferons exist, but interferon alpha (IFN-α), interferon beta
(IFN-β), and interferon gamma (IFN-γ) are among the better-understood types.
Virus-infected cells make IFN-αand IFN-βas chemical alarms that stimulate
nearby uninfected cells to mount antiviral defenses. IFN-γis made by certain
lymphocytes, especially NK cells and certain T cells, and stimulates a range of
innate and adaptive immune system effects that help combat viruses, bacteria, and
parasites.
Interferons (IFNs):
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41. Unfortunately, many viruses block
interferon signaling in infected cells.
This is a factor with Ebola viruses,
cold-and gastroenteritis-causing
adenoviruses, influenza A viruses,
polioviruses, and human
papillomaviruses, to name just a few.
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42. 42

43. •Becauseofitsroleinavarietyofmetabolicandotherphysiologically
essentialpathways,ironisavitalnutrientformostcells.Consequently,
ifaccesstoironislimited,thensoiscellgrowthandsurvival.
Normally,theamountoffreelyavailableironincirculationandwithin
ourtissuesiswellbelowthenecessaryamountmicrobesrequirefor
survival.Thisisthankstoouriron-bindingproteins.
•Oxygen-transportinghemoglobininourredbloodcellsisoneexample.
Othersincludeferritin,foundinmostcells;lactoferrin,seeninmilk,
tears,saliva,mucus,andneutrophilgranules;andtransferrin,foundin
bloodplasmaandextracellularfluids.
Iron-Binding Proteins:
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44. •Theyallsequesterirontoensurethatourowncellshaveanadequate
supplywhenneeded,whilealsodenyinginvadingmicrobeseasyaccess
toit.
•Theimportanceoflimitingfreeironlevelsisdemonstratedbythe
increasedfrequencyofbacterialinfectionsinpeoplethathave
thalassemiaandprimaryhemochromatosis(iscausedbyadefectinthe
genesthatcontrolhowmuchironyouabsorbfromfood),theseare
geneticconditionsthatincreasefreeironlevelsinthepatient.
Iron-Binding Proteins:
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45. •Perhaps not surprisingly, a number of pathogens have evolved ways to
steal iron from us.
•Some bacteria such as Neisseria gonorrhoeae have evolved ways to
capture our iron-binding proteins and then pull the iron out of them for
their own use.
•Many pathogenic bacteria make
siderophores, which are organic
molecules that pull iron from
our iron-binding proteins .
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46. •Hemolytic bacteria, like group A streptococci, break down red blood
cells to get to the iron rich hemoglobin inside.
•Other pathogens such as Borrelia burgdorferi, the bacterium that
causes lymedisease, use manganese in their metal-requiring enzymes
instead of iron, thereby circumventing our iron-sequestering defenses.
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48. •The acute-phase response is a rapid, systemic increase in various plasma proteins in
response to innate inflammation.
•IL-1, IL-6, and TNF-α are proinflammatory cytokines, meaning that they enhance the
inflammatory response in various ways.
•They signal to the hypothalamus to change the body’s thermostat, causing fever.
•They also signal to the liver hepatocytes to increase production of C-reactive protein
(CRP), mannan-binding lectin (MBL), proteins of the complement cascade,
Haptoglobin, Fibrinogen and other acute-phase proteins.
Acute -Phase Proteins:
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49. •Forexample,C-reactiveproteinbindstoacarbohydrateinthecellwallof
Streptococcuspneumoniae,mannan-bindinglectinbindstomannan
(mannose)onthesurfaceofmanybacteria,fungi,andprotozoa.
•Finally,manyacute-phaseproteinssignalbacktoimmunecells,
increasingthemigrationofnewneutrophilsandotherleukocytesfrom
thebonemarrowandenhancingtheirhoming,phagocytic,and
microbicidalfunctions.
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50. Functions:
1. Minimizes tissue injury.
2. All act either to limit the spread of
the infectious agents or to stimulate
the host response and promoting the
repair of damaged tissue.
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51. 51

52. Pattern Recognition Receptor (PRR) of Innate Immune cells:
•The first step of an immune response is that innate immune cells recognize foreign
material. In order to identify what is foreign, several components of the innate immune
arm detect certain carbohydrates or lipids on the surface of microorganisms.
•Components of the innate immune arm have receptors, called pattern recognition
receptors (PRRs), that recognize a molecular pattern, called apathogen-associated
molecular pattern (PAMP), that is present on the surface of many microbes but—very
importantly—is not present on human cells and is difficult for those microorganisms to
alter through mutation.
•By using this strategy, innate immune cells do not need a highly specific receptor for
each individual microbe strain but can still distinguish broad classes of foreign agents
from self.
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53. Pattern Recognition Receptor (PRR) of Innate Immune cells:
•These pathogen-associated molecular patterns (PAMPs) are molecules
shared by many microorganisms—but not present in mammals—and
therefore serve as “red flags” for phagocytes and other cells of innate
immunity.
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54. Figure:
Pattern recognition receptors (PRRs).
Pattern recognition receptors detect and
bind pathogen-associated molecular
patterns (PAMPs)
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55. Pattern Recognition Receptor (PRR) of Innate Immune cells:
•Therearetwoclassesofreceptors(Toll-likereceptorsandC-type
lectinreceptors)thatrecognizemicrobesthatareoutsideofcellsor
withinthecells’vesicles.
•Twootherclassesofreceptorsinthecytoplasmofcells(NOD-like
receptorsandRIG-Ihelicasereceptors)recognizemicrobesthathave
invadedthecell’scytoplasm.
•Mutationsinthegenesencodingthesepatternreceptorsresultina
failuretorecognizepathogensandpredisposetoseverebacterial,viral,
andfungalinfections.
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56. 56
NOD-like receptor = nucleotide-binding oligomerization domain-like receptors
RIG-I-like receptor = retinoic acid-inducible gene-I-like receptors

57. Pattern Recognition Receptor (PRR) of Innate Immune cells:
•ThemostimportantofthesePRRsaretheToll-likereceptors(TLRs).
Thisisafamilyof13receptorsfoundonthesurfaceofmanycells,
includingepithelialcellsandinnateimmunecells,suchasmacrophages
anddendriticcells.Eachofthe13TLRsrecognizesacoremicrobial
buildingblock(e.g.,endotoxinorpeptidoglycan),andtheresulting
signalactivatestranscriptionfactorsthatenhancethesynthesisof
proinflammatorycytokinesandcellsurfacemolecules.Theresultisa
rapidinnateimmuneresponse,triggeredbyaparticularmicrobeina
particularlocation.
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58. Function of TLRs:
Activation of the innate immune system.
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Functions of PAMPs:
1.Essential for survival of microbe.
2.Basic expressed on pathogen.
3.Mutational resistance.

59. Toll-like Receptors (TLRs):
•There are 13 different TLRs.
•Endotoxin (LPS) found on the surface of Gram negative bacteria
responsible for septic shock in hospitalized patients.
•LPS binds with protein present normally in the plasma called LPS-
binding protein.
•This binding protein transfer LPS to a receptor on the surface of
macrophage called CD14.
PRR example
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60. Figure:
Recognition of bacterial
lipopolysaccharide by innate immune
cells
*myeloid differentiation factor-2 (MD2)
*LPS-Binding Protein (LBP)
*Lipopolysaccharide (LPS)
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This figure just for preview

61. Next Lecture
Specific Host Defense
Mechanism
Any Questions ??!!!
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