Transcript Infection and Immunity

Infection and Immunity
What does a pathogen have to do?
• Infect (infest) a host
• Reproduce (replicate) itself
• Ensure that its progeny are transmitted to
another host
Mechanisms of
Transmission
• Aerosols - inhalation of droplets, e.g.
Rhinoviruses, the 'Common Cold Virus' or
Adenoviruses.
• Faecal-Oral - e.g. Astroviruses, Caliciviruses;
these viruses cause acute gastroenteritis.
• Vector-borne - e.g. in Arthropods such as
mosquitos, ticks, fleas: Arboviruses.
• Close personal contact - especially exchange of
bodily fluids: Sex; Blood, e.g. Herpesviruses
Entry into the Host
• Skin - dead cells, therefore cannot support virus
replication. Most viruses which infect via the skin require a
breach in the physical integrity of this effective barrier, e.g.
cuts or abrasions. Many viruses employ vectors, e.g. ticks,
mosquitos or vampire bats to breach the barrier.
• Respiratory tract - In contrast to skin, the respiratory tract
and all other mucosal surfaces possess sophisticated
immune defence mechanisms, as well as non-specific
inhibitory mechanisms (cilliated epithelium, mucus
secretion, lower temperature) which viruses must
overcome.
•
Entry into the Host
• Gastrointestinal tract - a hostile
environment; gastric acid, bile salts, etc
• Genitourinary tract - relatively less hostile
than the above, but less frequently exposed
to extraneous viruses (?)
• Conjunctiva - an exposed site and relatively
unprotected
Sites of virus entry
Transmission patterns
• Horizontal Transmission: Direct person-toperson spread.
• Vertical Transmission: Relies on PERSISTENCE
of the agent to transfer infection from parents
to offspring. Several forms of vertical
transmission can be distinguished:
• 1.Neonatal infection at birth, e.g. gonorrhorea,
AIDS.
• 2.Infection in utero e.g. syphilis, CMV, Rubella
(CRS), AIDS.
• 3. Germ line infection - via ovum or sperm.
Primary Replication
•
Having gained entry to a potential host, the
virus must initiate an infection by entering a
susceptible cell. This frequently determines
whether the infection will remain localized at the
site of entry or spread to become a systemic
infection
Localized Infections
• Viruses
Primary Replication
• Rhinoviruses
U.R.T.
• Rotaviruses
Intestinal epithelium
• Papillomaviruses
Epidermis
Systemic Infections
Virus
Primary Replication Secondary Replication
Enteroviruses
Intestinal epithelium
Lymphoid
tissues, C.N.S.
Herpesviruses
Oropharynx or
G.U.tract
Lymphoid cells,
C.N.S.
Spread Throughout the Host
• Apart from direct cell-cell contact, there are
2 main mechanisms for spread throughout
the host:
• via the bloodstream
• via the nervous system
via the bloodstream
• Virus may get into the bloodstream by direct
inoculation - e.g. Arthropod vectors, blood
transfusion or I.V. drug abuse. The virus may travel
free in the plasma (Togaviruses, Enteroviruses), or
in association with red cells (Orbiviruses), platelets
(HSV), lymphocytes (EBV, CMV) or monocytes
(Lentiviruses). Primary viraemia usually proceeds
and is necessary for spread to the blood stream,
followed by more generalized, higher titre
secondary viraemia as the virus reaches other target
tissues or replicates directly in blood cells
via the nervous system
• spread to nervous system is preceded by
primary viraemia. In some cases, spread
occurs directly by contact with neurons at the
primary site of infection, in other cases via the
bloodstream. Once in peripheral nerves, the
virus can spread to the CNS by axonal
transport along neurons (classic - HSV).
Viruses can cross synaptic junctions since
these frequently contain virus receptors,
allowing the virus to jump from one cell to
another
Cell/Tissue Tropism
• Tropism - the ability of a virus to replicate
in particular cells or tissues - is controlled
partly by the route of infection but largely
by the interaction of a virus attachment
protein (V.A.P.) with a specific receptor
molecule on the surface of a cell, and has
considerable effect on pathogenesis. Many
V.A.P.'s and virus receptors are now known.
Secondary Replication
• Occurs in systemic infections when
a virus reaches other tissues in
which it is capable of replication, e.g.
Poliovirus (gut epithelium - neurons
in brain & spinal cord) or
Lentiviruses (macrophages - CNS +
many other tissues). If a virus can
be prevented from reaching tissues
where secondary replication can
occur, generally no disease results.
:
Virus:
Localized Infections:
Primary Replication:
Rhinoviruses
U.R.T.
Rotaviruses
Intestinal epithelium
Papillomavirus
Epidermis
es
Systemic Infections:
Virus:
Primary Replication:
Enteroviruses
Intestinal epithelium
Herpesviruses
Oropharynx or
G.U.tract
Secondary
Replication:
Lymphoid tissues,
C.N.S.
Lymphoid cells, C.N.S.
Incubation periods of viral infections
Influenza
1-2d
Chickenpox
13-17d
Common cold
1-3d
Mumps
16-20d
Bronchiolitis,croup
3-5d
Rubella
17-20d
Acute respiratory
disease
5-7d
Mononucleosis
30-50d
Dengue
5-8d
Hepatitis A
15-40d
Herpes simplex
5-8d
Hepatitis B
50-150d
Enteroviruses
6-12d
Rabies
30-100d
poliomyelitis
5-20d
Papilloma
50-150d
Measles
9-12d
HIV
1-10y
Types of Infection
• Inapparent infection( Subclinical
infection) .
• Apparent infection:
• Acute infection
• Persistent Infection
Chronic infections
Latent Infection
Slow virus infections
Chronic Infection
• Virus can be continuously detected ;
mild or no clinical symptoms may be
evident.
Latent infection
The Virus persists in an occult, or cryptic,
from most of the time. There will be
intermittent flare-ups of clinical disease ,
Infectious virus can be recovered during
flare-ups . Latent virus infections typically
persist for the entire life of the host
Slow virus infection
• A prolonged incubation period, lasting
months or years, daring which virus continues
to multiply. Clinical symptoms are usually not
evident during the long incubation period .
Overall fate of the cell
• The cell dies in cytocidal infections
this may be acute (when infection is brief and selflimiting) or chronic (drawn out, only a few cells
infected while the rest proliferate)-Cytocidal
effect
• The cell lives in persistent infections
this may be productive or nonproductive (refers to
whether or not virions are produced) or it may
alternate between the two by way of latency and
reactivation - Steady state infection
Special cases
• Transformation-Integrated
infection (Viruses and Tumor)
• Apoptosis
Types of Viral infections at the cellular level
Type
Virus production
Fate of cell
Abortive
-
No effect
Cytolytic
+
Death
Persistent
Productive
+
Senescence
Latent
-
No effect
DNA viruses
-
Immortalization
RNA viruses
+
Immortalization
Transforming
Mechanisms of viral cytopathogenesis
Inhibition of cellular protein
synthesis
Inhibition and degradation of
cellular DNA
Polioviruses, HSV,
poxviruses, togaviruses
herpesviruses
Alteration of cell membrane
structure
Glycoprotein insertion
Syncytia formation
Disruption of cytoskeleton
permeability
Inclusion bodies
All enveloped viruses
HSV, VZ virus, HIV
HSV, naked viruses
Togaviruses,
herpesviruses
Rabies
Toxicity of Virion components
Adenovirus fibers
3. Viral Immunopathology
Viral Immunopathogenesis
• Influenza-like symptoms( IFN, lymphokins):
•
•
•
•
•
DTH and inflammation(Tcell, PMNs):
Immune-complex disease(AB, complement):
Hemorrhagic disease( T cell,AB, Complement):
Postinfection cytolysis( T cells): enveloped viruses
Immunosuppression: HIV; CMV; measlesvirus and influenza
Persistence
Long term persistence of virus results from
two main mechanisms:
• a) Regulation of lytic potential
• b) Evasion of immune surveillance
Persistence vs. Clearance
Antiviral Immunity
Overview of the Immune System
Components of the Immune
System
Nonspecific
Humoral
complement,
interferon,
TNF etc.
Cellular
macrophages,
neutrophils
NK cell
Specific
Humoral
antibodies
Cellular
T cells; other
effectors cells
Innate or Nonspecific
Immunity
Innate or Nonspecific
Immunity
• Anatomic and Physiologic Barriers:
Intact skin / Mucus membrane
Temperature /Acidity of gastric juices
Protein factors
• Phagocytic Barriers : 3 major types of
phagocytic cells
• Inflammatory Barriers and fever
• Mucociliary clearance
IFN
• Interferons are proteins produced by
cells infected with viruses, or exposed to
certain other agents, which protect other
cells against virus infection or decrease
drastically the virus yield from such cells.
Interferon itself is not directly the antiviral agent, but it is the inducer of one or
many anti-viral mechanisms
• Anti-tumor and regulation of immunity
Interferon inducing agents
• (1) Viruses.
• (2) dsRNA is a potent inducer, both viral
intermediates, and synthetic polyI-C.
• (4) Certain Bacterial infections, and the
production of endotoxin.
• (5) Metabolic activators/inhibitors.
Mitogens for gamma induction, also a
variety of tumor promoters induce IFNs. ,
in particular PTA-phorbol tetradecanoate
acetate, butyrate, dexamethasone
Properties of human interferons
Property
IFN-alpha
IFN-beta
IFN-gamma
Principal cell
source
Epithelium
leukocytes
Fibroblasts
Lymphocytes
genes
>20
1
1
Introns in genes
no
no
yes
induction
Viruses dsRNA
Viruses dsRNA
Immune
activation
Glycosylation
no
yes
yes
Stability at pH2
stability
stability
labile
Function
Antiviral
infection
activation of NK
cell
anti-tumor regulation of
enhancement of CMI
immunity
Activities of interferon
Antiviral actions
Interferons initiate an antiviral state in cells
Interferons block viral protein synthesis
Inferons inhibit cell growth
Immunomodulatory actions
Interferons-alpha and IFN-beta activate NK cells
Interferons-alpha activates macrophages
Interferons-gamma activate macrophages
Interferons increase MHC antigen expression
Interferons regulate the activities of T cells
Other actions
Interferons regulate inflammatory processes
Interferons regulate tumor growth
Mechanism of action
• Release from an initial infected cell occurs
• IFN binds to a specific cell surface receptor on
an other cell
• IFN induces the “antiviral state” : synthesis of
protein kinase, 2’5’ oligoadenylate synthetase,
and ribonuclease L
• Viral infection of the cell activates these
enzymes
• Inhibition of viral and cellular protein synthesis
occurs
Diseases currently treated with
IFN-alpha and IFN-beta
• hepatitis C
• hepatitis B
• papilloma warts and early trials with cervical
carcinoma
• Kaposi sarcoma of AIDS,
• colon tumors
• kidney tumors ( usually in combination with other
drugs).
• Basal cell carcinoma
• Breast cancer combined with tamoxifan.
Nature killer/ NK cell
•NK cells are Activated by IFN-alpha/beta
•NK cells are Activated by IFN-alpha and IL-2
and
Activate macrophage
•NK cells target and kill virus infected cells
NK cell
Macrophages
• Macrophages filter ciral particles from
blood
• Macrophages inactivate opsonized virus
particles
• Macrophages present viral antigen to
CD4 T cells
Complement
• Enhancing neutralization of Antibody
• Enhancing phagocytosis of virus
particles
• Lysis
Specific immunity
Active/passive
Overview of Specific immunity
• specific recognition and selective
elimination of foreign molecules.
• Involves specificity, diversity, memory, and
self/nonself recognition.
The Role of MHC
• The molecular basis of antigen recognition
by T cells is well understood. The TcR
recognizes short antigen-derived peptide
sequences presented in association with self
MHC class I or MHC class II molecules at
the surface of an antigen presenting cell
(APC).
The Role of MHC
• T cell recognition, therefore, involves direct
cell-cell contact between the antigenspecific TcR on the T lymphocyte and an
MHC compatible cell which presents the
processed antigen in association with
surface MHC molecules.
The Role of MHC
• The finding that self MHC molecules are involved
in the recognition of antigen by T lymphocytes led
to the concept of "MHC restriction" of T cell
responses, and pointed to the important role that
products of the major histocompatibility complex
play in the cell mediated immune response. The
major histocompatibility complex consists of a
cluster of genes, most of which encode products
with immunologically related functions.
The Role of MHC
• In humans, the MHC is located on the short arm of
chromosome 6 and spans approximately 4 megabases of
DNA. It can be divided into three regions termed class I,
class II and class III:
• The class III region contains genes which encode a number
of complement components and the tumour necrosis factor
cytokines, amongst other molecules.
• MHC class I molecules consist of a polymorphic, MHCencoded, membrane-spanning heavy chain, and a
monomorphic light chain, beta2-microglobulin.
• MHC class II molecules consist of a heterodimer of two
MHC-encoded, membrane-spanning proteins, the alpha and
beta polypeptide chains of the MHC class II molecule.
The Role of MHC
MHC class I molecules present
antigen to CD8+ T cells
MHC class II molecules present
antigen to CD4+ T cells
T cells
T cells are essential for controlling enveloped and noncytolytic viral
infections
T cells recognizes viral peptides presented by MHC molecules on cell
surfaces
Antigenic viral peptides can come from any viral protein
TH1 CD4 responses are more important than TH2 responses
CD8 cytotoxic T cells respond to viral peptide-class I MHC protein
complexes on the cell surface
TH2 CD4 responses are important for the maturation of antibody
response
TH2 CD4 responses may be detrimental if they prematurely limit the
TH1 inflammatory and cytolytic responses
Antibody
Antibody neutralizes extracellular virue:
it blocks viral attachment proteins
it destablilizes viral structure
Antibody opsonizes virus for phagocytosis
Antibody promotes killing of target cell by the complement cascade
and antibody-dependent cellular cytotoxicity
Antibody resolves lytic viral infections
Antibody blocks viremic spread to target tissue
IgM is an indicator of recent or current infection
IgG is more effective than LgM
Secretory IgA is important for protecting mucosal surfaces
Humoral Immunity
Antibody dependent cellular
cytotoxicity or ADCC
Antibody
IgG
Function
Memory
Blood and
tissue
IgM
Primary
response
Clear viruses in
blood
-
IgA
Mucus
immunit
y
C: classic
pathway
C : C3 pathway
+++
-
-
-
+
placenta
+++
-
-
ADCC
++
-
-
Antibody
• Neutralization antibody
• Other antibody
Passive Immunity
• A high titer of antibody against a
specific virus
• A pooled sample from plasma donors
that contains a heterogeneous mixture
of antibodies with lower titer