Microbiology- a clinical approach by Anthony
Strelkauskas et al. 2010
Chapter 15: The innate immune response

Innate immune responses are host defense
mechanisms of limited specificity.
◦ They are based on pattern recognition.
◦ They are of paramount importance for fighting off
infectious disease.
◦ They protect the newborn to a great deal.
BARRIERS
CELLULAR AND
CHEMICAL
RESPONSES
Innate
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Limited specificity
Immediately
available,
preformed or
recruited within
hours after
infection
No memory
Adaptive
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
Specific
Takes several
days to develop
Has memory
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Barriers - prevent the entry of pathogens
Cellular and chemical mechanisms - destroy
pathogens
Initiates the adaptive response
Responses are triggered by damage to cells or
tissues.
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Natural barriers are the
first line of defense.
◦ Not exclusively defense
mechanisms and have other
functions

Three types of barriers:
◦ Mechanical
 Skin
 Mucous membranes
 Other barriers – lachrymal
apparatus, saliva, and
epiglottis
◦ Chemical
◦ Microbiological
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Skin is covered by microorganisms.
It is impermeable to entry by microorganisms.
◦ Entry requires breaks in the skin.
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Skin is divided into two layers:
◦ Epidermis – no access to blood so only localized infection
occurs
◦ Dermis – access to blood vessels so infection here can
become systemic
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Loss of skin can lead to serious infection.
◦ Burn injuries (Pseudomonas aeruginosa)
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Found on inner body surfaces with access to
the outside of the body
◦ Respiratory tract
◦ Gastrointestinal tract
◦ Genitourinary tract
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Primary function is to keep tissues moist.
They can also trap microorganisms in mucus.
◦ The mucociliary escalator of the respiratory tract

Lacrymal apparatus
◦ Protects the eyes from
entry by pathogens.
◦ Causes tears to flush
across eye
 Tears contain
antimicrobial factors

Saliva
 Cleans teeth and tissues of the oral cavity
 Prepares food for digestion
 Inhibits microbial growth
▪ Contains antimicrobial factors
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Prevents aspiration of food into the lungs.
Also prevents entry of microorganisms into the
lungs.
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Many chemical substances that with
antimicrobial activity are secreted by the body:
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Sebum
Perspiration
Gastric juice
Urine
Barrier defense is not their primary function.

Sebum

Perspiration
◦ By sebaceous glands
◦ Forms protective layer on
skin.
◦ Contains unsaturated fatty
acids and organic acids
◦ Inhibit bacterial growth by
low pH.
◦ Regulates body
temperature and eliminates
waste
◦ Barrier against
microorganisms in two
ways:
 Flushes them from the skin
 Contains lysozyme

Gastric juice
◦ Stomach acids
◦ Enzymes
◦ The harsh chemical
environment limits microbial
growth.
◦ Some organisms survive this
environment
 Helicobacter pylori resides in the
stomach.

Urine
◦ Used to secrete waste
material from the body
◦ Barrier against
microorganisms in two ways:
 It is acidic.
 Its flushing action prevents
attachment
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Body surfaces are populated by
normal microbiota.
Bacteria >>> fungi >> protozoa
Mucosal surfaces more
populated than skin
Sites close to body entrances
are more populated
Combined weight ~ 1 kg
Outnumber host by 1014 : 1, host
cells by > 10:1
Microbial gene pool (99%
bacterial) ~ 150-fold > than
that of the host
Important role in defense
◦ Compete for nutrients
◦ Produce antimicrobials
◦ Stimulate the immune system
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Cellular response:

Chemical responses via soluble molecules:
◦ Epithelial cells: secretion of antimicrobials, alerting
the host
◦ Phagocytes: phagocytosis
◦
◦
◦
◦
Inflammation
Fever
Interferon
The complement system

Epithelial cells have receptors that recognize
pathogen associated molecular patterns
◦ Toll-like receptors (TLRs)
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TLRs are activated when microbial products
binds to them.
Their activation leads to the release
antimicrobial and pro-inflammatory substances
◦ Antimicrobial peptides
◦ Cytokines, for example interleukin 1 (IL1)
◦ Chemokines, for example CXCL8
Microbial Products
(LPS, PG, etc)
TLR: Toll-like receptor
(pattern recognition)
LPS: lipopolysaccharide
PG: peptidoglycan
TLR
Antimicrobial
Peptides
Cytokines, Chemokines

The innate immune response relies on white
blood cells
◦ Derived from bone marrow stem cells
◦ Numbers correlate with stages of infection.
◦ Identified by a complete blood count and differential
blood test.

2 types of white blood cell:
◦ Granulocytes
 Neutrophils, eosinophils, basophils
◦ Agranulocytes or mononuclear cells
 Monocytes (  macrophages) and lymphocytes
NK cells
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Have granular cytoplasm and multilobed nuclei
There are three types:
◦ Neutrophils
Basophils
Eosinophils
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Phagocytic cells
Guard skin and mucous membranes
Derived from bone marrow and mature there
Circulate in blood for 6 to 10 hours
Make up about 50 - 70% of white blood cell
population
Exit rapidly into skin and mucosa when needed
guided by chemotaxis and diapedesis
◦ Remain in tissues for up to 2-6 days
◦ Die via apoptosis (cell suicide) if not further of use
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From progenitor cells in
bone marrow
Short life span – a few
days
Small numbers circulate in
blood
Activated by bacteria,
viruses, and parasites
(using TLRs)
Carry receptors for IgE
Binding of IgE causes
release of histamine
Histamine amplifies innate
immune reactions.
Basophils
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Very small numbers
circulate in blood
Numbers increase in
parasitic infection and
allergic response
Primary defense to
parasite infection
Powerful enzymes that
attack parasites
Recognize parasites via IgE
and release their granules
onto the large parasites
Modulate inflammatory
response
Eosinophils
The fluke had been covered by IgE (immunoglobulin or antibody type E)
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Have cytoplasmic granules that are not easily seen
Nucleus is more homogenous, not fragmented
Types of agranulocytes:
◦ Monocytes
 Macrophages
◦ Natural killer cells
◦ Lymphocytes (part of
adaptive immune system)
http://www.meded.virginia.edu/courses
/path/innes/nh/wcb.cf

Monocytes
◦ Derived from bone
marrow cells
◦ Only small numbers
circulate in the blood:
 Circulate in a nonphagocytic
form
 Numbers increase during
infection.
◦ Guided to the site of
tissue damage by
chemotaxis:
 Second cell type to arrive at
the site of infection.
◦ Differentiate into
powerful phagocytic
macrophages at the site.
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Macrophages
◦ Develop from monocytes
◦ Have a longer life time
and can differentiate
into specialized resident
macrophages
 Liver Kupffer cells
◦ Responsible for the
phagocytosis of:
 Bacteria
 Fungi
 Protozoa
◦ Can ingest apoptotic cells
◦ Very important in alerting
and activating the
adaptive immune system
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Two types of chemical mediators of the innate
immune response:
◦ Cytokines
◦ Chemokines

They are both produced at the onset of and
throughout the infection.
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Low molecular weight proteins
Released by a variety of cell types
◦ Release is in response to stimuli associated with
infection.

Induce and regulate innate and adaptive
immune responses
Affect the cells that produce them and other
cells
React with specific receptors on target cells
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Have overlapping functions
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Activity is concentration dependent
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◦ Alter activity of those cells
◦ Induce or inhibit effects of other cytokines
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Specialized cytokines that appear at the
earliest time during infection:
Attract defensive cells to the site of infection
Released by many types of immune cells
Released in response to bacterial or viral
infection as well as tissue damage
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Mast cells
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Dendritic cells
◦ Mostly in tissues exposed to the external environment under skin
and mucosa
◦ Responsible for allergic responses and parasitic infections
◦ Filled with granules that contain huge amounts of bioactive
mediators (e.g. histamine, leukotrienes and cytokines which are
pro-inflammatory; proteases)
◦ Work with complement system
◦ Found in all tissues
 Ie.g. in skin: Langerhans cells
◦ Regulate both the innate and adaptive immune response
◦ Take up antigen (sample the environment) and bring it to the lymph
nodes
◦ Have long membranous extensions, large surface area for
interaction with foreign material and lymphocytes
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Natural killer cells
◦ Kill tumor cells and cells infected with viruses, bacteria, fungi, and
protozoa
◦ Secrete cytokines to activate other immune cells
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Induce apoptosis in the target cell
◦ Programmed cell death
Leads to self destruction of the DNA while the
cell itself shrinks.
Clean death
Contrasts necrosis where the cell dissolves and
spills out its content
One NK cell can kill many infected host cells
◦ Serial killer
A.
B.
C.
D.
E.
Low pH in the
stomach
Bile acids in the lung
High pH in the urine
All of the above are
correct.
None of the above
is correct.
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It is primarily carried out by:
◦ Neutrophils
◦ Macrophages
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Both are attracted to site of tissue
destruction by chemotaxis.
◦ Neutrophils arrive first.
◦ Then monocytes – differentiate into macrophages as
they arrive.
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Chemotaxis
Adherence
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Ingestion
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◦ Attachment
◦ Improved by
opsonins
◦ Pseudopodia
formation
◦ Phagosome
Digestion and
killing
◦ Phagolysosome
◦ Antimicrobial
peptides
◦ Oxidative burst

(Excretion)
Granulocyte attacking Bacillus spec.
Granulocyte attacking Candida spec.

Some bacteria can resist phagocytosis.
◦ Produce toxins or enzymes to destroy phagocytic cells
 leukocidins
◦ Produce capsules that inhibit adherence
◦ Destroy the phagolysosome membrane and escape into
the cytoplasm
◦ Resist digestion
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Some patients can be deficient in phagocytosis
◦ Chemotherapy and/or radiation patients
◦ Transplant patients under immunosuppressive therapy
 Bone marrow transplant
◦ Immunocompromised patients
A.
B.
C.
D.
E.
Antimicrobial
peptides
Enzymes
Oxidative burst
IL1
All are correct.
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The normal physiological response to trauma
◦ Helps destroy pathogens
◦ Involved in tissue repair and replacement
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Four symptoms
All related to
vasodilation
Redness (rubor)
Pain (dolor)
Heat (calor)
Swelling (tumor)
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Vasodilation is the cornerstone of
inflammation.
◦ Involves localized reactions
◦ Characterized by increased blood flow
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The injured area becomes redder and warmer.
Surrounding areas become swollen by fluid
from blood vessels.
◦ Swelling puts pressure on local pain receptors.
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Also delivers clotting elements
◦ These can wall off the affected area.
◦ This can prevent the spread of infection.
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Occurs in response to the release of chemical
signals
Goes along with making endothelial cells and
phagocytes more sticky and promoting diapedesis
Biomolecules providing the chemical signals:
◦ Histamine – found in many cell types
 Enhances vasodilation
◦ Kinins – released from damaged tissue
 Recruit more phagocytic cells
◦ Prostaglandins – intensify effects of histamine and kinins
 Help migration of phagocytes out of the blood and into tissues
◦ Leukotrienes – produced by mast cells
 Promote adherence of phagocytic cells
◦ Cytokines (e.g. IL1 and TNF alpha)
◦ Complement factors
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Only seen in acute illness
Acute-phase proteins are produced by liver
cells that have been activated by IL6
◦ Activated macrophages release IL6
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Levels of acute phase proteins can go up over
1000 fold within hours
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C-reactive protein (CRP)
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Mannose-binding protein
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Fibrinogen
◦ Binds to phospholipids, functions as opsonin
◦ Binds to mannose sugars on bacterial and fungal
membranes
◦ Coating improves phagocytosis
◦ Also activates the complement system
◦ Promotes clotting
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Fever is a systemic rise in body temperature.
◦ Clinically – oral temperature above 37.8˚ C, rectal
above 38.4˚ C.
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Often accompanies and augments inflammation
Can accompany certain immune responses
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Induced by IL1 (and assisted by IL6 and TNF)
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◦ Most types of tissue injury cause fever
◦
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IL-1 acts on hypothalamus
Causes release of prostaglandin
Alters body thermostat
Fever continues as long as IL-1 is present
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Fever is a good thing.

However, unchecked fever can be dangerous.
◦ It increases the speed of host defenses.
◦ It causes the patient to rest.
◦ It is unfavorable for many microbes and microbial
agents
◦
◦
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◦
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Causes denaturation of proteins
Inhibits CNS function
Causes dehydration and electrolyte imbalance
In extreme cases it can lead to coma
Antipyretics are used to prevent temperature
from rising too high.
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The complement system is a complex system of
over 30 proteins
◦ Includes active components (C1 – C9)
◦ Stabilizators
◦ Control proteins
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Main producers of complement proteins are liver
cells and fibroblasts
Complement is activated immediately upon invasion
by pathogens.
Initial steps of complement activation include a
series of enzymatic cleavages to turn inactive
precursors into bioactive factors (C1 – C5a)
This is followed by structural assembly of an
membrane attack complex that forms pores in the
target cell (C5b – C9n).
Panel A: © Sucharit Bhakdi
Panel B: © Shreiber et al., 1979.
Originally published in The Journal
of Experimental Medicine, 149: 870 – 882.

Three pathways to activate complement

Three major outcomes
◦ Classical: antigen-antibody complexes
◦ Alternative: spontaneous attack of the microbial
surface (human cells are able to inactivate this
pathway)
◦ Lectin-binding: lectins bind to microbial sugars and
then trigger complement activation (e.g. MBL or
mannose binding lectin).
◦ Pore formation on the microbial target membrane (or
viral envelope)
◦ Opsonization by covering the microbial target so that
it can be easily recognized by phagocytes
◦ Inflammation by activating endothelial cells and
recruiting phagocytes
mannose
MBP
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Pathogens have defenses against complement.
◦ Encapsulation
 Discourages formation of membrane attack complex
◦ Some Gram-negative bacteria lengthen surface
glycolipids.
 Prevents membrane attack
◦ Some Gram-positive bacteria release enzymes to
cleave C5a.
 Limit amplification of innate responses by complement.

Some people are genetically deficient for
complement components.
◦ They are more prone to infections.
◦ C3 deficiencies are the most dangerous because it is
so central.
 Increase in pyogenic infections
◦ Terminal (C5 – C9) complement factor deficiencies
 Increase in Neisseria infections
A.
B.
C.
D.
E.
Improved
phagocytosis
Inflammation
Killing of the
microbial target.
All of the above
None of the above.
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Production of interferon alpha and beta is a
host response to viral infection.
Produced by and released from virus-infected
cells
Any cell can make it, is base line defense
 Moves to uninfected neighboring cells
 Causes them to produce antiviral proteins
 Makes uninfected cells resistant to infection

Some people are genetically predisposed to
infection
◦ Genetic defect in oxidative burst formation in
ohagocytes
◦ Genetic deficiency in TLRs
◦ Inability to produce cytokines or chemokines
◦ Deficiency in complement proteins
◦ Genetic deficiency in interferon production
◦ and many more causes...
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The innate immune response is a response to any type of
infection with limited specificity
This response is composed of both mechanical and
chemical barriers as well as cellular and chemical
responses that are part of the innate response, including
phagocytosis, antimicrobial peptides and lipids,
inflammation, complement activation, fever, and the
production of interferon.
Cellular responses are carried out by epithelial cells and
white blood cells
Host defense cells use Toll-like receptors to identify
nonself antigens.
Diapedesis is the process whereby white blood cells
leave the blood and migrate into tissues to reach the
site of the infection.
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A variety of cytokines and chemokines are produced
throughout the innate response.
Phagocytosis is one of the most important parts of the
innate response and involves attachment, ingestion, and
digestion.
Inflammation involves vasodilation and results in
redness, pain, heat, and swelling.
Complement activation involves a cascade of proteins
that result in the destruction of a bacterial cell,
improved phagocytosis, and inflammation.
The complement cascade can be initiated in three ways:
the classical pathway, the alternative pathway, and the
lectin-binding pathway.
There can be a genetic predisposition to infection.