Transcript Virus

Medical Virology
Lecture 01
Youjun Feng
Pathogenesis & Control of Viral Diseases
Youjun Feng
Center for Infection & Immunity, Zhejiang University School of Medicine
[email protected]
Pathogenesis of viral disease
Principles of viral disease
Iceberg concept of virus infection
Cell responses
Lysis of cell
Inclusion body formation
or
Cell transformation
or
Cell dysfunction
Viral multiplication
without visible change or
incomplete viral
maturation
Exposure without
attachment and/or
cell entry
Host responses
Death of organism
Classic and
sever disease
Moderate severity
Mild illness
Infection without
clinical illness
(asymptomatic
infection)
Exposure
without
infection
Entry into the host
Sel-replication
Spread to another host
What does a pathogen have to do?
Pathogenesis of viral disease
Steps in viral pathogenesis
Stages in virus-host interaction
Entry into the host
Primary replication
Spread in the host
Cell and tissue tropism
Secondary replication
Cell injury and persistence
Host immune response
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, mosquitoes or vampire
bats to breach the barrier.
Respiratory tract - In
SARS-CoV
Flavivirus
contrast to skin, the
respiratory tract and all other
mucosal surfaces possess
sophisticated immune defence
mechanisms, as well as nonspecific 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
Horizontal Transmission
DIRECT person-to-person spread
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
VS
Vertical Transmission
Relies on PERSISTENCE of the
agent to transfer infection from
parents to offspring
Neonatal infection at birth
e.g. gonorrhoea, AIDS
Infection in utero
e.g. syphilis, CMV,
Rubella (CRS), AIDS.
Germ line infection
via ovum or sperm.
Transmission of viruses
Aerosols
Parental
Direct contacts
Sex
Primary vs. secondary replication
Localized Infections:
Virus:
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.
From primary to secondary replication
Spread Throughout the Host
1- via the direct cell-cell contact
2- via the bloodstream
3- via the nervous system
The direct cell-cell contact
Cell/Tissue Tropism
• Tropism - the ability of a virus to replicate in particular cells or
tissues
•
controlled partly by the route of infection
• largely by the interaction of a virus attachment protein (V.A.P.) with a
specific receptor molecule on the surface of a cell,
• has considerable effect on pathogenesis
• Many V.A.P.'s and virus receptors are now known
Virus entry
is highly specific for the host and for the cell to be infected
Human
Immunodeficiency
Virus (HIV)
Co-receptor:
Chemokine
Receptors CCR-5/CXCR4
Main-receptor:
CD4 antigen
CD4+ T lymphocytes
Monocytes
Macrophages
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),
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.
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
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.
Localized Infections:
Virus:
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.
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
Outcomes of viral infections
acute, self limiting
chronic
Locally restricted
(z. B. Rhinitis, Enteritis)
Latent, reactivation (Phases
without viremia)
(e.g.: Herpesviruses)
Chronic persistent
(permanent virus production)
(e.g.: Hepatitis B and C)
Systemic
local replication => Viremia
(eg. Masern)
Active progression
(e.g.: HIV)
Patterns in acute and persistent infections
raute 7/2002
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
Productive
+
Senescence
Latent
-
No effect
DNA viruses
-
Immortalization
RNA viruses
+
Immortalization
Persistent
Transforming
Mechanisms of viral cytopathogenesis
Inhibition of cellular protein
synthesis
Polioviruses, HSV,
poxviruses, togaviruses
Inhibition and degradation of
cellular DNA
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
Viral Immunopathogenesis
• Influenza-like symptoms (IFN, Lymphokins)
• DTH and inflammation (T-cell, PMNs)
• Immune-complex disease (AB, Complement)
• Hemorrhagic disease ( T-cell, AB, Complement)
• Post-infection cytolysis ( T-cells): Enveloped viruses
• Immuno-suppression: HIV; CMV; Measles virus and Influenza
Viral pathogenesis
the seven steps from entry to disease
1 Replication at the
site of entry
2 Lymph node
HSV
VZV
3 Primary viremia
4 Replication sites
5 Secondary viremia
6 Replication sites
7 Transmission to
other hosts
Cytomegalovirus
Time and date:
20:00-22:00
2015.05.08
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Pathogenesis of viral disease
Host immune responses
The two columns of immunity
immunity
constitutional, skin
defensins
constitutional, blood complement
reactive, blood
interferons
raute 5/2001
Time table
of innate and specific immunity
complement
interferon a/b
NK cells
CD4 lymphocytes
CD8 lymphocytes
antibodies
days after infection
raute 5/2001
Early phase of immunity
Infectious agent
Epithelial barrier
polymorphonuclear Monocytes
NK cells
?
Granulocytes (PMN)
draining
Lymphnode
Interleukin/Cytokin
Balance
Polarization of the
T-cell response
Antigen-specific responses
Toll-like receptors
Surveillance systems for microbes
Surveillance systems for microbes
pathogen associated microbial patterns (PAMP)
pattern recognition receptors (PRR)
Toll-like receptor pathways
TLR4 has been reserved for
gram-negative bacteria
Inhibition of Toll-like receptor pathways
Hengel, H., Koszinowski, U. H., Conzelmann, K. K., 2005
Prevention and treatment of
viral infection
Antiviral chemotherapy
Antiviral chemotherapeutic agents
• Antiviral drugs are available to treat only a
few viral diseases.
• The reason for this is the fact that viral
replication is so intimately associated with
the host cell that any drug that interferes
significantly with viral replication, is likely
to be toxic to the host
Targets for chemotherapeutic agents
•
•
•
•
•
Attachment to host cell
Uncoating –(amantadine)
Synthesis of viral mRNA-(interferon)
Translation of mRNA-(interferon)
Replication of viral RNA or DNA- (nucleoside
anologues)
• Maturation of new virus proteins-(protease
inhibitors)
• Budding , Release
Diseases for which effective therapy is available
• AIDS: Cocktail therapy
(Zidovudine + Lamivudine + protease inhibitors)
• Influenza: Amantadine
• Herpes simplex virus: Acyclovir
• Varicella-Zoster virus: Acyclovir
• Cytomegalovirus : Gancyclovir, Foscarnet
• Respiratory syncytial virus: Ribavirin
Nucleotide analogues
• Nucleotide analogues competes with
normal nucleotide for incorporation
into viral DNA or RNA.
Prevention and treatment of
viral infection
Interferons
human interferons
source
inductor
antiviral action
localization
IFN-b
all cells
all cells
IFN-g
T-lymphos
viral dsRNA
viral dsRNA
antigen/mitogen
+++
+++
+
chromosome 9 chromosome 12 chromosome 9
number of subtypes
Function
IFN-a
22
Antiviral
infection
activation of
NK cell
1
1
anti-tumor regulation of
enhancement of CMI
immunity
Interferon-inducing dsRNA: 30 bp
Mechanism of action
• Release from an initially-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
interferon a and b: gene products to remember
2’, 5’-oligo adenylate cyclase
RNA dependent protein kinase
Interferon
occupies receptors
on vicinal cells
30 bp dsRNA induces
production of
a & b Interferon
interferon activates > 100 genes
2‘, 5‘-oligo
adenylate synthetase
activation of an
endonuclease
RNA dependent
Protein kinase (PKR)
phosphorylation &
inactivation of
arrest of
Inhibition of virus replication
raute 10/2002
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.
Summary
1. To know the transmission routes of viral infection;
2. To understand the clinical patterns of viral infection and
disease;
3. To grasp the pathogenesis of virus;
4. To know the properties and anti-viral activities of
interferon
Self control questions
1. Which one of the following substances is NOT released by activated helper T cells?
A. Alpha interferon
B. Gamma interferon
C. Interleukin-2
D. Interleukin-4
2. Which one of the following statements concerning interferons is LEAST accurate?
A. Interferons are proteins influence host defenses in many ways, one of which is the induction of an
antiviral state
B. Interferons are synthesized only by virus-infected cells
C. Interferons inhibit a broad range of viruses, not just the virus that induced the interferon
D. Synthesis of several host enzymes is induced by interferon in target cells
3. Each of the following statements concerning interferon is correct EXCEPT:
A. Interferon inhibits the growth of both DNA and RNA viruses
B. Interferon is induced by double-stranded RNA
C. Interferon made by cells of one species acts more effectively in the cells of that species than in the cells
of other species
D. Interferon acts by preventing viruses from entering the cell
4. Please describe the Sites of virus entry.
5. Please describe the mechanisms of virus transmission from person-person.
6. How does the virus spread throughout the host?
7. What determines the cell/tissue tropism for a virus?
8. Please describe the patterns in acute and persistent viral infections.
9. What are the mechanisms for the anti-viral activities of interferon?
10. Term explanation: Horizontal Transmission & Vertical Transmission;
Thank you!