05 M301 Host Def NS 2011 - Cal State LA
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Transcript 05 M301 Host Def NS 2011 - Cal State LA
Nonspecific Defenses
of the Host
Innate Immunity
Nonspecific Host Defense
Resistance: ability to ward off disease
through our defenses
Susceptibility: vulnerability, lack of
resistance to disease
Innate Immunity: non-specific defense,
protect us from pathogens in general;
natural, born with defense
Adaptive immunity: protects from specific
MO, develops after exposure to specific
MO
Innate vs. Adaptive Immunity
Innate and Adaptive immune systems do
not operate independently of each other
Very inner-connected in activities
First Line of Defense
Intact skin and mucous
membrane
Mechanical factors provides formidable
physical barrier to MOs
Chemical factors
Intact Skin: Mechanical
Factors - Keratin
Continuous sheet of
closely packed epithelial
cells
Consists of connective
tissue, inner dermis and
outer epidermis
Top layer has
waterproofing protein
called keratin
When epithelial surface
broken subcutaneous
infection may develop,
frequently by
Staphylococcus aureus
Mucous Membranes – Mucous
Outer epithelial and inner connective
tissue layers; line digestive, respiratory,
urinary, and reproductive tracts
Goblet cells in epithelial layers secrete
mucous to prevent drying out, act to trap
MOs
Some pathogens (T. pallidum, M.
tuberculosis, S. pneumoniae), survive in
these moist secretions; if present in
sufficient numbers able to penetrate
membrane
Mucous Membranes - Cilia
Cells of RT mucous membranes contain cilia
Move synchronously to propel inhaled dust
and MOs trapped in mucous, upward
toward the throat away from LRT
Eye Lacrimal Apparatus Washing
Manufacture and drain away tear secretion
By continual washing action, helps keep
MOs from settling on surface of eye
If something irritates eye, the lacrimal
glands secrete heavily to wash away
irritating substance
Cleansing Mechanisms
Similar cleansing action of saliva washes
MOs from teeth, mucous membranes in
mouth
Nose has mucous coated hairs that filter
air; trap MOs, dust, pollutants
Epiglottis covers larynx during swallowing,
prevent MOs from entering LRT
Flow of urine through urethra provides
mechanical cleansing of urinary tract
Intact Skin: Chemical
Factors
Sebum - produced by oil glands provides
protective film over skin; unsaturated
fatty acids inhibit growth of bacteria and
fungi due to low pH of skin
Perspiration - produced by sweat glands
contributes to high salt content of skin,
make it osmotically unfavorable for MOs
Lysozyme – in perspiration, tears, saliva,
nasal secretions and tissue. What is the
activity of lysozyme?
Chemical Factors
Gastric juice - produced by stomach, very
acidic and destroy most bacteria and
bacterial toxins; food particles may
protect enteric pathogens from acid
Defensins - cysteine rich antimicrobial
peptides produced by skin
Cryptocidins – antimicrobial peptides
produced by epithelium of intestine
Normal flora - protect colonization by
potentially pathogenic bacteria. How?
Second Line of
Defense:
Phagocytosis
Process of engulfing and ingesting
foreign particles by WBCs
Blood – plasma, formed elements:
RBCs - erythrocytes
Platlets - thrombocytes
WBCs - leukocytes
WBCs
Divided into two basic types:
Granulocytes
Agranulocytes
Both may be phagocytic
Complete Blood Cell (CBC) Count
Determine – RBC,
WBC, Differential
Count
Leukocytosis increase
leukocytes, often in
bacteria infection
Leukopenia - some
diseases cause
decrease
leukocytes
Differential WBC
Count -percentage
of each type by
counting 100 WBCs
WBC Function
Neutrophils (PMNs) - highly phagocytic, leave blood,
enter infected tissue, destroy foreign substances
Basophils - release histamine and heparin,
inflammatory response, hypersensitivity reaction
Eosinophils – somewhat phagocytic, ingest antigenantibody complexes, increased during parasitic
infection, hypersensitivity reaction
Lymphocytes - mainly in lymphoid tissue, some in
circulating blood, important in antibody production
(B cell) and modulating immune response (T cell)
Monocytes - poorly phagocytic until stimulated by
infection; then move into tissue and differentiate
into macrophages (highly phagocytic)
WBC Function
During infection both neutrophils (PMNs)
and monocytes (become macrophages)
migrate to infected area
Neutrophils - first cell arrive at infected
site and predominant cell found during
initial stage of infection
In latter stages of infection monocytes
predominate
Phagocytosis
Migration to infection site; chemotaxis (1)
Attachment of MO to phagocyte (1)
Ingestion of MO (2)
Killing of MO (3-7)
Phagocytosis:
Chemotaxis
The process of adherence facilitated by
chemotaxis
Attraction of phagocytes to MOs via
chemical factors (cytokines) released by
certain WBCs, damaged tissues, microbial
products or peptides derived from the
complement cascade
Cell Cytokine
Activated macrophages serve many other
functions against infections including
leukocyte recruitment and tissue
remodeling
These functions mediated by cytokines
Cytokines - chemicals produced by innate
immunity, mainly by PMNs, macrophages
and NK cells
Endothelial cells and epithelial cells may
also produce cytokines
Cytokines serve to communicate (via signal
transduction) information among
inflammatory cells, responsive tissue cells
Phagocytosis: Attachment
Adherence of MO via receptor on phagocyte
Cell receptor called Pattern Recognition Receptor
Recognizes MO structure - PAMP (Pathogen
Associated Molecular Pattern not present on host
Toll Receptor and Signal
Transduction Pathways
Pattern recognition
receptor also called tolllike receptor originally
ID in Drosophila innate
immune response
Binding of PAMP to tolllike receptor triggers a
signaling cascade (signal
transduction) in which
transcription factors
translocated into nucleus
leads to gene expression
involved innate response
Activates phagocytic cell
LPS Activation of Innate
Immunity
Example of LPS
(PAMP) which binds to
toll-like receptor to
trigger a subsequent
signal transduction
pathway
Leads to expression of
genes involved in
innate immune
response
Attachment of Encapsulated MOs
MO capsule protects
against phagocytosis
MO adherence difficult,
occur by two mechanisms:
1. Non-immune or surface
phagocytosis – phagocyte
traps MO against a rough
surface, cannot slide away
2. Opsonization – MO coated
by opsonin (antibody or
complement)
Phagocytic cell receptor for
opsonin act as bridge to
promote attachment of MO
to phagocyte
Phagocytosis: Ingestion
MO engulfed by
pseudopods
Phagocytic membrane
fold inward enclosing MO
in phagosome (vacuole)
Phagosome pinch off,
enter cytoplasm to fuse
with lysosome
Digestive enzymes
present in lysosome kill
the MO
But not all MO killed by
lysosomal enzymes
Phagocytosis: Killing
Killing MO via digestive enzymes in lysosomes
Other killing mechanisms - intracellular and
extracellular:
In plasma membrane is oxidase enzyme activated to
produce reactive oxygen intermediates (ROIs) such
as superoxide radical; process called respiratory or
oxidative burst
Nitric oxidase synthase in cytosol activated to
produce nitric oxide (NO); diffuses into
phagolysosome, activated by acid pH, interact with
ROIs to generate a highly toxic peroxynitrite
radical
All these also released from activated phagocytes
to kill extracellular bacteria
Microbicidal Mechanisms of
Phagocytes
Second Line of Defense:
Inflammation
Damage to body tissue trigger
inflammatory response
Four symptoms of inflammation: redness,
pain, heat, and swelling
Also sometimes loss of function
Inflammation has three functions:
Destroy injurious agent, remove it from body
If destruction not possible, wall off injurious
agent
Repair or replace damaged tissue
Inflammation: Three Stage Process
Tissue Damage
causes release of
histamine,
prostoglandin,
kinin;
vasodilation,
permeability of
blood vessels
WBC Migration
of phagocyes to
injury site,
phagocytosis of
MO
Tissue Repair last stage of
inflammatory
process
Inflammation: Tissue
Damage
Vasodilation - increase diameter blood
vessels, increase blood flow to injured
area; redness and heat
Vascular permeability - permits defensive
substances present in blood enter injured
area; edema, swelling; pain from swelling,
nerve damage, toxins
Clotting elements - delivered to injured
area, clots prevent spreading of MOs;
result in localized collection of pus formed
by breakdown of body tissue (forms
abscess)
Inflammation: WBC Migration
Blood flow decreases, phagocytic cells stick to
blood vessels (margination), cells squeeze through
walls of vessels to damaged area (diapedesis)
PMN’s arrive first, attracted by chemotactic
factors released from damaged tissue
Leokocytosis promoting factor released from
inflamed tissue, production of additional PMNs
from bone marrow
Monocytes enter inflamed area; differentiate to
macrophages, larger, more phagocytic than PMNs
PMNs & macrophages engulf large number MOs and
tissue, die; collection of dead cells & various tissue
fluids = pus
Pus formation continue until infection subsides
Inflammation: Tissue Repair
Process by which tissues replace dead or
damaged cells
Second Line of Defense: Fever
Systemic response to infection
Body temperature controlled by hypothalamus
Antigens such as LPS cause phagocytic cells to
release leukocyte pyrogen (IL-1), hypothalamus
release prostoglandins that reset body thermostat at
higher temperature
Blood vessel constriction, increased metabolism and
shivering all help to increase temperature; shivering
sign body temperature rising
As infection subsides, heat losing mechanisms such
as vasodilation and sweating occur
Fever beneficial to inhibit bacterial growth, intensify
interferon, help body tissue to repair
But if body temperature too high (>450 C) may
damage or be lethal
Second Line of Defense: Interferon
IFN produced, released from virus infected cell
IFN binds to receptor on neighboring cell
Via signal transduction pathway, induce antiviral proteins;
block virus replication, protect cell
IFN host specific but not viral specific
Second Line of Defense:
Complement
Group of proteins found in normal blood serum
Important in both non-specific and specific
antigen-antibody defense
Function to attack and destroy invading MOs,
stimulate inflammatory response
Proteins act in sequence or cascade reactions
In sequence of steps, proteins activate one
another by cleaving next protein in series
Cleaved proteins have new enzymatic or
physiological function
Complement: Three Pathways
Three different,
interconnected
pathways of
Complement
activation
1. Classical
2. Lecitin
3. Alternative
(Properdin)
Complement: Classical Pathway
Via antigen-antibody
complex
Activates
Complement
component C1 to
activated C1 complex
Activates C4, C2 to
form another
activated complex
This complex next
activates C3, cleaved
into C3a and C3b
Complement: Lectin
Pathway
The Lectin pathway initiated by binding of
serum protein, mannose-binding lectin (MBL)
produced during inflammation
MBL binds to mannose residues on
glycoproteins or carbohydrates on surface
of MOs
Functions like an activated C1-like complex
Complement: Alternate
(Properidin) Pathway
Activated by bacteria cell
wall polysaccharides
interaction with properdin
factors to activate C3 by
cleavage into C3a and C3b
C3b produced by all three
pathways involves
components C5 through C9 in
a membrane attack complex
that punches a hole in MO
leading to cytolysis (process
called complement fixation)
C3a and cleavage products
from C5, C6, and C7
contribute to development of
acute inflammatory response
Results of Complement
Fixation
Complement Stimulation of
Inflammation
Second Line of Defense: Natural
Killer (NK) Cell
Lymphocytes activated by:
1. Antibody coated cells
2. Cells infected by viruses,
intracellular bacteria
3. Cells lacking class I MHC
NK cells express inhibitory
receptors that recognize class I
MHC molecules (self)
NK cells activated by target
cells lacking class I molecules
(non-self)
Some viruses down regulate
expression of class I molecules
Activated NK cells lyse target
cells by releasing granules that
induce apoptosis of target cell
NK Activity With Normal Cell
NK Activity With Cell Lacking
MHC Class I
Components of Innate Immunity
Innate Stimulates Adaptive Immunity
Class Assignment
Textbook Reading:
Chapter 2 Host- Pathogen Interaction
B. Pathogenesis of Infection
Host Resistance Factors
Key Terms
Learning Assessment Questions
Review, Review, Review!
MICR 301 Midterm Exam
Tuesday, Oct. 25, 2011; 8:30-9:40am
Specimen Collection & Processing through
Host Defense
Lecture, Reading, Key Terms, Learning
Assessment Questions
Case Study: Viral 1 (WNV), Viral 2 (HBV),
Bacterial 1 (M. tb)
Exam Format: Objective Questions (M.C.,
T/F, ID) and Short Essay