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
2nd stage
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2. Introduction:
• 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.
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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: innate and 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
1 Speed of action Rapidly (Minutes to Hours)
2 Development of memory No
3 Specificity of recognition Broad
4 Self/non-self-discrimination Perfect
5 Activity 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)
7 Major 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
8 Major Histocompatibility
Complex
No MHC restricted
9 Receptor Have receptors called Pattern Recognition Receptors
(PRR)
10 Exposure to the same
pathogen
No increase in response upon repeated exposure to
the same pathogen
11 Response Uptake and clearance, danger signaling
12 Target Groups of pathogens
13 Anatomic and chemicals Skin, mucosa, chemicals & pH
14 APCs Not require
15 Coordinator 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-Lysozyme present 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-Lactoperoxidase in milk has bactericidal action.
5-Gastric juice is produced by the glands of the stomach.
6-Vaginal secretions 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. • The normal microbiota prevents pathogens from colonizing the host by
competing with them for nutrients (competitive exclusion), by producing
substances that are harmful to the pathogens, and by altering conditions that
affect the survival of the pathogens, such as pH and oxygen availability.
• The presence of normal microbiota in the vagina, for example, alters pH,
thus preventing overpopulation by Candida albicans, a pathogenic yeast that
causes vaginitis.
• In the large intestine, E. coli bacteria produce bacteriocins that inhibit the
growth of Salmonella and Shigella.
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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. • For its second line of defense, the body uses an enormous number of
cells and chemicals.
• These defenses rely on the destructive powers of cells called
phagocytes and natural killer cells, on the inflammatory response (is a
nonspecific response that is triggered whenever body tissues are
injured), and on a variety of chemical substances that kill pathogens
and help repair tissue. Fever is another nonspecific protective response.
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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
hypothalamus of 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. • Inflammation is an innate immune response that tends to develop
when our tissues are damaged, either from physical factors like trauma or
burns, or from infectious agents.
• Although a physical injury often introduces an infectious agent, such
as when a skin cut allows a pathogen to gain entry, the injury could also
be aseptic, meaning it doesn’t introduce an infectious agent.
Inflammation:
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22. What's the difference
between infection and
inflammation?
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23. It has two types:
A) Acute inflammation:
Develops quickly and is short lived, Is usually beneficial, Important in
the second line of defense, dilation and increased permeability of the
blood vessels, migration of phagocytes, tissue repair.
B) Chronic inflammation:
Develops slowly and lasts a long time, Can cause damage to tissues.
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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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27. 27

28. Cellular second-line Defenses:
Although the physical defense barriers do an excellent job of keeping microbes out of
our bodies, we constantly suffer minor breaches of the physical defense barriers. A
paper cut, the cracking of dry skin, or even brushing our teeth may temporarily
breach the physical defenses and allow some microbes to enter the blood or
connective tissue.
However, we survive these daily attacks because ever-present cellular defenses can
kill invading microbes or remove them from the blood or tissues.
Still, if microorganisms enter blood through cuts in the skin, cellular defense
mechanisms come into play.
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**

29. Phagocytosis:
• Phagocytes are cells that literally eat or engulf other materials. They
patrol, or circulate through the body, destroying dead cells and cellular
debris that must be removed constantly from the body as cells die and
are replaced. Phagocytes also guard the skin and mucous membranes
against invasion by microorganisms. Being present in many tissues,
these cells first attack microbes and other foreign material at portals of
entry, such as wounds in skin or mucous membranes.
• If some microbes escape destruction at the portal of entry and enter
deeper tissues, phagocytes circulating in blood or lymph mount a
second attack on them.
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30. Several types of cells in the immune system engulf microorganisms
via phagocytosis, Which are mainly; Neutrophils, Macrophages,
Dendritic Cells & B Lymphocytes.
The Process of Phagocytosis:
• If an infection occurs, phagocytic cells use this four-step process to
destroy the invading microorganisms.
(1) Recognition,
(2) Adherence,
(3) Engulfment, and
(4) Intracellular killing.
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31. 31
Figure: Phases of Phagocytosis

32. Phagocytes: Neutrophils vs Macrophages:
* Neutrophils die and lyse after extended phagocytosis. This makes up the
characteristic properties of pus.
* Unlike the neutrophil, macrophage can present the antigenic fragments to the T cells
in the context of MHC class II molecules after engulfing the bacterial cells.
* Macrophages digested debris and allow insertion of microbial antigenic components
into the plasma membrane for presentation to lymphocytes in the immunological
response.
* Macrophages can live longer than neutrophils.
* Since macrophages are larger than neutrophils, they can phagocyte greater number of
invader pathogens than neutrophils.
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33. • Most macrophages can live for several months and can kill hundreds of different
bacteria before they die. That destroy not only microorganisms but also larger
particles, such as debris left from neutrophils that have died after ingesting bacteria.
Although macrophages take longer than neutrophils to reach an infection site, they
arrive in larger numbers.
• Macrophages can be fixed or wandering.
• Fixed macrophages remain stationary in tissues and are given different names,
depending on the tissue in which they reside .
• Wandering macrophages, like the neutrophils, circulate in the blood, moving into
tissues when microbes and other foreign material are present .
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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-dependent mechanisms of intracellular digestion are
activated as a result of this process.
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35. ● NADPH oxidase reduces oxygen (O2) to superoxide anion (.O2-)
, which generates hydroxyl radicals (.OH.) and hydrogen peroxide
(H2O2), which are microbicidal.
● Myeloperoxidase in the lysosomes acts on hydrogen peroxide (H2O2)
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.a Citrulline=a.a 35

36. • The lysosomal contents of phagocytes contain oxygen-independent degradative
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- α and IFN- β as chemical alarms that stimulate
nearby uninfected cells to mount antiviral defenses. IFN- γ is 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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43. • Because of its role in a variety of metabolic and other physiologically
essential pathways, iron is a vital nutrient for most cells. Consequently,
if access to iron is limited, then so is cell growth and survival.
Normally, the amount of freely available iron in circulation and within
our tissues is well below the necessary amount microbes require for
survival. This is thanks to our iron-binding proteins.
• Oxygen-transporting hemoglobin in our red blood cells is one example.
Others include ferritin, found in most cells; lactoferrin, seen in milk,
tears, saliva, mucus, and neutrophil granules; and transferrin, found in
blood plasma and extracellular fluids.
Iron-Binding Proteins:
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44. • They all sequester iron to ensure that our own cells have an adequate
supply when needed, while also denying invading microbes easy access
to it.
• The importance of limiting free iron levels is demonstrated by the
increased frequency of bacterial infections in people that have
thalassemia and primary hemochromatosis (is caused by a defect in the
genes that control how much iron you absorb from food), these are
genetic conditions that increase free iron levels in the patient.
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 lyme disease, use manganese in their metal-requiring enzymes
instead of iron, thereby circumventing our iron-sequestering defenses.
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47. 47

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. • For example, C-reactive protein binds to a carbohydrate in the cell wall of
Streptococcus pneumoniae, mannan-binding lectin binds to mannan
(mannose) on the surface of many bacteria, fungi, and protozoa.
• Finally, many acute-phase proteins signal back to immune cells,
increasing the migration of new neutrophils and other leukocytes from
the bone marrow and enhancing their homing, phagocytic, and
microbicidal functions.
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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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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 a pathogen-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:
• There are two classes of receptors (Toll-like receptors and C-type
lectin receptors) that recognize microbes that are outside of cells or
within the cells’ vesicles.
• Two other classes of receptors in the cytoplasm of cells (NOD-like
receptors and RIG-I helicase receptors) recognize microbes that have
invaded the cell’s cytoplasm.
• Mutations in the genes encoding these pattern receptors result in a
failure to recognize pathogens and predispose to severe bacterial, viral,
and fungal infections.
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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:
• The most important of these PRRs are the Toll-like receptors (TLRs).
This is a family of 13 receptors found on the surface of many cells,
including epithelial cells and innate immune cells, such as macrophages
and dendritic cells. Each of the 13 TLRs recognizes a core microbial
building block (e.g., endotoxin or peptidoglycan), and the resulting
signal activates transcription factors that enhance the synthesis of
proinflammatory cytokines and cell surface molecules. The result is a
rapid innate immune response, triggered by a particular microbe in a
particular location.
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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) 60
This figure just for preview

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