Download 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