Transcript Document

Infection and
Immunity of virus
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-to



person 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
cells,
Lymphoid
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
:
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
self-limiting) 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
Transforming
DNA viruses
-
Immortalization
RNA viruses
+
Immortalization
Mechanisms of viral cytopathogenesis
Inhibition of cellular protein
synthesis
Inhibition and degradation of
cellular DNA
Alteration of cell membrane
structure
Glycoprotein insertion
Syncytia formation
Disruption of cytoskeleton
permeability
Polioviruses, HSV,
poxviruses,
togaviruses
herpesviruses
All enveloped viruses
HSV, VZ virus, HIV
HSV, naked viruses
Togaviruses,
herpesviruses
Inclusion bodies
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 anti-viral agent, but it is the
inducer of one or many anti-viral
mechanisms
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,
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
anti-tumor regulation of
infection
enhancement of CMI
activation of NK immunity
cell
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 IL2 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
antigen-specific 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,
MHC-encoded, 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
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
C: classic
pathway
C : C3
pathway
placenta
+++
ADCC
IgM
Primary
response
Clear viruses
in blood
-
IgA
Mucus
immunit
y
-
-
-
+
+++
-
-
++
-
-
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