Immunity to Infectious Agents
Chun-Keung Yu, DVM, PhD
Department of Microbiology and Immunology
College of Medicine, National Cheng Kung University
April 20, 2010
Summary of Chapter 13
Immunity to viruses
• Innate immune mechanisms (interferon, NK cells, and
macrophages) restrict the early stages of infection and
delay spread of virus.
• As a viral infection proceeds, the adaptive (specific)
immune response unfolds.
• Viruses have evolved strategies to evade the immune
response.
• Responses to viral antigens can cause tissue damage.
(Immunopathology)
Innate (non-specific) immune response
to viral infection
• Body surface
• Early non-specific or innate immune
– Interferon (IFN)
• Type I IFNs (IFN α and IFN β) (virus-infected cells)
• Type II IFN or IFN γ (activated T and NK cells)
– Natural killer (NK) cells
– Macrophages
‘Danger’ Signal
dsRNA is a signature of viral replication
Activation of NF- λB and IFNs
4
Virus-infected cells
= resistant status
Bcl-2 and
caspase
cascade
eIF-2
Blocks
translation
of uninfected cells
Increase
expression of
MHC class I
and II, and
thus antigen
presentation
Killing signal
for CTLs
Major antiviral cells in early phrase
Plasmcytoid DC2
1.A major IFNα producer after viral infection
2. Toll-like receptor -3
< 2 days after viral infection
1.Cytolysis by perforingranzyme
2.IFN γ: protect uninfected cells
and activate macrophages
3.Mediate ADCC
IFNγ
1. Phagocytosis of virus and virus-infected
cells
2. Kill virus-infected cells
3. Produce antiviral molecules: TNFα, NO,
IFNα
Adaptive (specific) immune response
to viral infection
• Cytotoxic T lymphocytes (CTLs)
• Helper T (Th) cells
• Antiviral antibodies
Restrict virus spread in blood stream
(between cells and tissues)
Neutralization of infectivity
Classical and alternative pathways
By MAC
Via FcγRIII recognization and
perforin-dependent killing
T cell-mediated antiviral immunity
• Antibody response: CD4+ T cells help antibody class switching
and affinity maturation
• CD8+ CTLs
– All cells express MHC class I molecules
– Any viral protein can be processed and interacted with MHC
class I molecules
– MHC class I-restricted CD8+ CTLs destroy virus-infected
cells (perforin, granzymes, Fas-FasL)
– CD4+ T cell-derived IL-2: CD8+ T cell growth factor
CD4+ T cell-derived chemokines: recruit CD8+ T to site of
infection
– Prevention of re-infection (antibody > CTLs)
• Macrophages
– CD4+ T cells secrete IFNγ and TNFα to recruit and activate macrophages
Adaptive (specific) immune response to viral infection
9
7
5
6
8
IFNγ
IFNα and IFNβ
Neighboring
uninfected cells
1
3
4
2
Protection
Killing
Lymph nodes
and spleen
Blood and
infected tissues
IFNs
Activated T cells
are absent by the
2nd and 3rd weeks.
T cell memory
may last for many
years
Viruses have evolved strategies to evade
antiviral responses
• Evade recognition by antibody and T cells
– Antigenic variation
– Amino acid changes (nt sequence changes = mutation) on
proteins targeted by antibody and T cells
– HIV, FMDV, influenza virus (antigenic drift and shift)
• Disrupt interferon system
• Encode cytokine homologs (eg. vIL-10, vIL-6, vTNFR)
• Encode complement protein homologs
• Disrupt chemokine network
• Control the expression MHC molecules
Antigenic drift = slight antigenic change
Antigenic shift = radical antigenic change
Mediated cell attachment
Antibody to HA are protective
Internal
antigens are
relatively stable
Responses to viral antigens can cause
tissue damage (1)
• Immune complex
– Persistent or chronic infections with a large amounts of viral
antigen making antibody ineffective (non-neutralizing)
– Deposition in kidney or blood vessels (inflammation)
• Antibody-dependent enhancement (ADE) of virus
infection
– Weakly neutralizing antibody
– Fc receptor-mediated uptake antibody-virus complexes by
macrophages
– Dengue virus infection: cross-reactive antibodies from
different subtypes; DHF, DSS
• CTL response causes tissue damage
– LCMV in mice, chronic active hepatitis in humans
(are related to immune status)
T cell-mediated
T cell depletion
No death
Responses to viral antigens can cause
tissue damage (2)
• Infection of immunocompetent cells
– Death of cell (eg., HIV), ineffective immunity
– Transformation leading to neoplasia (Epstein-Bar virus, HTLV-1)
• Autoimmunity
– Exposure of ‘hidden’ antigens as a result of virus-induced inflammatory
response
– eg., Theiler’s virus and murine hepatitis virus infection of the CNS; myelin
become the targets for antibody and T cells.
• Molecular mimicry
– ‘self’ protein is recognized by the immune response since it is homologous
to a viral protein
– Breakdown of immunological tolerance to cryptic self antigens leading to
attack on host tissues
– eg., Coxsackie B virus-induced cardiomyopathy
gp120
Integration of host
cell’s genomic DNA
Summary of Chapter 14
Immunity to bacteria and fungi
• Mechanisms of protection from bacteria can be deduced from
their structure and pathogenicity.
• Lymphocyte-independent (innate) bacterial recognition pathways
have several consequences.
• Antibody provides an antigen-specific protective mechanism.
(specific)
• Ultimately most bacteria are killed by phagocytes.
• Infected cells can be killed by CTLs.
• Successful pathogens have evolved mechanisms to avoid
phagocyte-mediated killing.
• The response to bacteria can result in immunological tissue
damage.
• Fungi can cause life-threatening infections.
• Yersinia pestis: killed ¼ of European
population in the Middle Ages.
• Myocbacterium tuberculosis: infect 1/3 of
the world population
Immune defenses against pathogenic
bacteria are determined by their
• Surface chemistry
• Mechanism(s) of pathogenicity
• Extracellular or intracellular parasite
Different immunological mechanisms have evolved to
destroy cell wall structure of different groups of bacteria
There are four types
7
8. Impede C’
and
phagocytosis
Targets for Ab
6
5. Compound cell wall extremely
resistant to breakdown
3
1
4. Lysis by cationic proteins and complement
Killing by phagocytosis
2. Lysosomal enzymes
Asterisk (*) are recognized by the innate immune
system as a non-specific ‘danger’ signal
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© 2005 Elsevier
Neutralizing antibody
is protective
Protection requires cellmediated immune
responses
Antibody and cellmediated responses
are required
• The first lines of defense do not need antigen
recognition: skin, epithelial surfaces, fatty acid, ciliary
action in trachea, low pH in stomach and vagina.
– Commensals limits pathogen invasion
• The second line of define is mediated by recognition
of bacterial components. (innate)
– Microbial components bearing ‘pathogen-associated molecular
pattern’ (PAMPs) (‘danger’ signal)
– PAMPs are recog(nized by the ‘pattern recognition molecules’
of the innate immune system
• Collectins and ficolins
• Toll-like receptors
• NOD proteins
Pattern recognition molecules
• Toll-like receptor (TLR) family
– At least ten TLRs: TLR1, 2, 4, 5, 6 and 9
– Express on phagocytes, dendritic cells, epithelial
cells with a different combination
• Mannose receptor
• Scavenger receptors
• Complement
• C-reactive protein
• Mannose-binding lectin
• Surfactant protein A in lung
LPS is the dominant activator of innate immunity in Gram (-) bacteria
Endotoxin shock
1
2
Acute
phase
response
4. release
3. transfer to
II
TLR4
TLR4
I
III
Other bacterial components as
immune activators
• Cell well components: peptidoglycans and lipoteichoic
acids → TLR2, 1, 6
• Lipid components from mycoplasma, mycobacteria, and
spirochetes → LBP, CD14
• Mycoplasma lipoproteins → TLR2/6
• Flagellin → TLR5
• DNA (CpG motifs) → TLR9 (express in phagosomes)
• Peptidoglycans of G(+) and G(-) → NOD-1 and NOD-2
proteins in cytosol
1. Inflammation
2. Activation of clotting system, fibrin formation
= innate
Limit bacterial spreading
4
1. Recognition
molecules in blood
3
2.Alternative
5. PAMPs
8
6. Recognition
receptors on cells
i.e., TLRs
7
1
What happen after bacterial recognition?
•
•
•
Activation of the alternative pathway of complement
– Lytic complex (C5b-9): kill bacteria with outer lipid bilayer
– C5a: attracts and activates neutrophils and cause mast cell degranulation (histamine
and LTB4)
– C3 derivatives: opsonization
Proinflammatory cytokines production
– TNF, IL-1 (from macrophages): increase adhesive properties
– Chemokines: attracts leukocytes
– TNF, IL-1, IL-6: induce acute phase responses (complements…)
– IL-12, IL-18: stimulate NK cells to release IFN γ to activate macrophages
Induction of lymphocyte-mediated response (innate to acquired)
– Immature DCs in periphery migrate to draining lymph nodes to prime T cells
– Activated macrophages at site of infection act as APC to further activate effector T
cells
– TLR activation induces a local environment rich in IFN γ, IL-12, and IL-18 which
favors TH1 pathway
Alternative
complement
pathway only
Most bacteria are killed by phagocytes
• A few Gram-negative bacteria are killed by
complement
• Most bacteria are killed by phagocytes
– Neutrophils in blood
– Resident macrophages in tissues
• Phagocytes are attracted by bacterial components
and complement products to site of infection
– Cellular composition: pyogenic = acute, rich in
neutrophils; granuloma = chronic, rich in macrophages
PAMPs
LPS : TLR4
Flagellin : TLR5
LP/PG : TLR2/1/6
Pattern recognition molecules
Complement
components
Complement-fixing antibody:
IgM > IgG3 > IgG1
Bacterial components
Trigger uptake, cytokine secretion, and kill mechanisms
Killing pathways of phagocytes
• Oxygen dependent
– Reduction of oxygen to superoxide anion,
formation of free radicals and toxic derivatives
– Formation of nitric oxide (inducible NO
synthase)
• Oxygen independent
–
–
–
–
Defensins
Acidification of phagosomes
Lysosome
Lactoferrin and Lactoferricin
Macrophage killing enhanced on activation by (1) microbial
products via TLRs (induce TH1 response) and (2) cytokines
(IFNγ)
NK cells, NK T cells, and
macrophages produce IFNγ.
Th1 T cells are the major
source of IFNγ.
In lymph nodes
TLRs
Direct cell contact
High
IL-12 low
High IL-10
and TGF β
Th2
In site of infection
Treg
Bacteria-infected cells can be killed by CTLs
(viruses, Listeria spp)
Cross-presentation
MHC class I (ER); See Fig7.11
FasL -Fas
(Mtb)
MHC class I
Other T cell populations can contribute to
antibacterial immunity
• Non-conventional T cells (cytotoxic activity
and secrete IFNγ)
• γδ T cells
– Epithelial surfaces
– Recognize phospholigands
• CD1-restricted αβ T cells
– Recognize glycolipids
– Presented by CD1 (non-polymorphic homologs of
MHC class I) on DC
Some tissue cells express
antimicrobial mechanisms
• Secrete defensins by epithelial cells
• Infected cells as targets of CTLs
• Restrict the growth of intracellular
microbial
1. Toxins
inhibit
chemotaxis
2. Capsule repel
attachment
3. Inhibit phagosomelysosome fusion;
Inhibit proton pump
4. Catalase
neutralize H2O2
8. Resident in
cytoplasma
5. Resistant coating
6. LAM blocks
IFN γ signal
7. Block antigen
presentation
Pathogenic bacteria escape the effects of antibody
1.Avoid the effects of antibody
2.Alter antigenic composition
(b)
(4) Adsorb and deplete
local Ab
(a
)
(3)
(c)
(2)
(1)
Pathogenic bacteria escape the effects of
complement
O antigen on
LPS
shedding
Sialic acid
Factor H and I
Smooth surface of G(-)
C5a protease Group A Strept
Resist
insertion
© 2005 Elsevier
Response to bacteria can result in
immunological tissue damage
•
•
•
•
Endotoxin shock
Schwartzman reaction
Koch phenomenon
Superantigens induce massive cytokine
release
Superantigens
of G(+) bacteria
G(-)
bacteria
Diffuse intravascular coagulation (DIC)
Defective clotting, increase vascular
permeability, loss of fluid in tissues, full in
blood pressure, circulatory collapse,
hemorrhagic necrosis
(1)
(2
)
A cytokine-mediated tissue damage in a site of previous
inflammation
Local inflammation and upregulation
of cytokine receptors by IFN γ
secreted by NK and NK T cells
Systemic cytokine release (TNF)
(hemorrhagic rash)
Systemic infection
Extracellular
Intracellular