Download of virus infection

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
Downloaded from: StudentConsult (on 30 August 2006 05:13 AM)
© 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