Transcript No Slide Title

Virus-Host Interactions
Allan Zajac, Ph.D
Lab: 446 BBRB Telephone: 5-5644
email: [email protected]
Text: Medical Microbiology 4th edition
Pathogenesis Chapter 46
Antivirals Chapter 47
Viruses and Disease Chapter 65
Immunity to Infections Chapter 14
Vaccines Chapter 15
Virus Pathogenesis
Patterns of Infections
Outcomes of Infections
Virus-Host Interactions
Antiviral Immunity
Strategies for Evading the
Immune Response
Control of Viral Infections
Vaccines
Antiviral Drugs
• Multiple viruses can cause the same
symptoms
– Hepatitis
– Common Cold
• The same virus can cause multiple
diseases
– HSV
– EBV
CELL RESPONSE
HOST RESPONSE
Lysis of Cell
Death of Organism
Inclusion Body Formation/
Cell Transformation/
Cell Dysfunction
Classical and Severe
Disease
Moderate Severity
Mild Illness
Viral Multiplication
Without Visible
Change or Incomplete
Viral Maturation
Infection Without
Clinical Illness
(Asymptomatic
Infection)
Exposure Without
Attachment and/or
Cell Entry
Exposure Without
Infection
THE ICEBURG CONCEPT
VIRUSES ARE OBLIGATE INTRACELLULAR PARASITES;
THEY NEED TO INFECT PERMISSIVE HOST CELLS
Routes of viral transmission
Mode of Transmission
Example
Method of Control?
Aerosol/Saliva.....
Respiratory of salivary
spread
Influenza Virus
EBV
Measles
Mumps
Transmission difficult to control
Fecal-Oral
Polio
Rotavirus
Hepatitis A
Controllable by public health
measures
Venereal spread
HSV
HIV
HPV
Controllable by appropriate
precautions
Zoonoses
Insect-Human
Animal-Human
Animal-Insect-Human
Dengue
Rabies
Lassa
Hantavirus
Yellow fever
Human infection can be
controlled by controlling vectors
(insects) and/or by controlling
animal infection. No (or rare)
human to human transmission
Mousepox/ Polio/ Measles Overhead
ACUTE
Rhinovirus
Influenza
Yellow Fever
LATENT PERSISTENT
Herpes simplex
Varicella-zoster
Measles-SSPE
CHRONIC PERSISTENT
Hepatitis B
LCMV in Newborn Mice
Latent infection slide show
Examples of latent infection followed by periodic reactivation
Example
Mechanism of
establishment
Maintenance
Stimulatory
mechanism for
reactivation
Herpes simplex
virus in sensory
ganglion neurons
Limited
transcription and
possibly replication
of genome
Non-replicating
episome
Neuronal activation
or damage
Epstein-Barr virus
in B lymphocytes
Limited
transcription of viral
genome
Replication of viral
DNA as episome
Antigen activation
or other stimuli of B
cells
Papillomavirus in
basal cells of
epidermis
Limited
transcription of viral
genome
Replication of viral
DNA as episome
Differentiation of
basal cells
IMMUNE RESPONSES TO VIRAL INFECTIONS
Medical Microbiology pg 131-135
Innate Response……..the first line of defence
Interferons
Activated Macrophages
Natural Killer Cells
Adaptive Response…….specifically targets the infection
B cells/ Antibodies
CD8 T cells/ Cytotoxicity and Cytokines
CD4 T cells/ Cytokines (and cytotoxicity)
Neutralizing Antibodies Bind to the
Influenza Virus Hemagglutinin
and Block Viral Attachment
Rhinovirus 14 complexed with neutralizing
antibodies (blue), as solved by cryo-electron
microscopy and image reconstruction
courtesy of Tim Baker. Purdue University
FIGURE 1: (TOP) Cryoelectron micrograph (gray) and computer enhanced image (in color) of spherical human rhinovirus 14 particles (yellow &orange)
saturated with a neutralizing monoclonal antibody (blue) (mAb17 IgG2a, directed against the NIM-IA site). The particle is assembled from 12 pentameric
subunits. The Fc portion of the IgG is not visible, apparently because it is too mobile to produce reinforcement in the enhancement stage. This is the first direct
evidence in support of the pentamer bridging hypothesis proposed by Mosser et al. in 1989 (A morph animation illustrates corresponding density in a previous,
inconclusive 3D cryoelectron microscopy dataset). Pentamer bridging by an antibody molecule is illustrated by an animated model.
(BOTTOM) Each bivalent IgG molecule (red, heavy chains, purple,light chains) bridges two canyons on adjacent pentamers (yellow) of the virus shell. (The
hypothesized correspondance of the IgG model to the 3D cryoelectron microscopy image reconstruction is shown by a morph animation.) Binding of IgG
molecules inhibits attachment by preventing insertion of cellular receptor into the canyon. Mobility of the Fc region is indicated by blurring in the region farthest
from the virus surface.
Adaptive/Virus-Specific Immune Responses
Effector
CD8+ T cell
Effector
CD4+ T cell
Y
Non-Lytic
Infection
Lytic Infection
Detrimental Effects of Virus-Specific
Immune Responses
• Immune Complex Disease
• Immunopathology
• Antibody Dependent Enhancement of
Infection
Viral strategies for evading the
immune system (Text Table 14-4)
•Restricted gene expression; latency
•Infection of sites not readily accessible to the immune
system
•Antigenic variation
•Downregulation of surface molecules required for T cell
recognition
•Interference with antiviral cytokines
•Immunological tolerance
Viral strategies for evading the
immune system
Antigenic variation
Antibody escape variants (lentivirus)
CTL escape variants (HIV, EBV, HBV)
TCR antagonism (HIV, HBV)
Influenza: A segmented negative sense RNA virus
that undergoes antigenic DRIFTS and SHIFTS
Two mechanisms generate variations in
influenza surface antigens.
Antigenic Drift:
The accumulation of point mutations
enventually yields a variant protein
that is no longer recognized by
antibody to the original antigen
Antigenic Shift:
May occur by reassortment of an
entire ssRNA between human and
animal virions infecting the same cell
(only four of the eight RNA segments
are illustrated)
Viral strategies for evading the
immune system
Restricted gene expression; latency
HSV and VZV (neurons)
EBV (B cells)
HIV (resting T cells)
Infection of sites not readily accessible to the
immune system
HSV, VZV, measles, rubella (CNS)
papillomavirus (epidermis)
CMV (salivary gland)
Viral strategies for evading the
immune system
Downregulation of surface molecules required for
T cell recognition
MHC class I (Adenovirus, CMV, HSV, HIV)
MHC class II (CMV, HIV, measles)
LFA-3, ICAM-1 (EBV);
CMV protein
removes class I
from ER
Proteasome
Degraded
Viral strategies for evading the
immune system
Interference with antiviral cytokines
Adenovirus (TNF)
Adenovirus, EBV, HIV (Type I IFN)
EBV vIL-10 (blocks synthesis of IL-2 and IL-10)
Poxviruses (encode gene products that inhibit action
of many cytokines)
Immunological tolerance
Exhaustion or clonal deletion/anergy of virus-specific
CTL during chronic virus infection (e.g. HBV)
Viral strategies for evading the immune system
Restricted gene expression; latency
Infection of sites not readily accessible
to the immune system
Antigenic variation
Downregulation of surface molecules
required for T cell recognition
Interference with antiviral cytokines
Immunological tolerance
HSV and VZV (neurons);
EBV (B cells); HIV (resting T cells)
HSV, VZV, measles, rubella (CNS);
papillomavirus (epidermis); CMV
(salivary gland)
Antibody escape variants (lentivirus);
CTL escape variants (HIV, EBV, HBV);
TCR antagonism (HIV, HBV)
MHC class I (Adeno, CMV, HSV, HIV);
MHC class II (CMV, HIV, measles);
LFA-3, ICAM-1 (EBV);
Adenovirus (TNF); Adenovirus, EBV,
HIV (Type I IFN); EBV vIL-10 (blocks
synthesis of IL-2 and IL-10);
Poxviruses (inhibit action of many
cytokines)
Clonal deletion/anergy of virus-specific
CTL during chronic infection (e.g. HBV)
Controlling Viral Infections
• Public Health Measures
-Sanitation
-Vector Control
-Behavioral Changes
• Vaccines
• Antiviral Drugs
Vaccines
• How can we prevent infectious diseases?
• The goal of vaccination is to induce a long
lived immune response that prevents disease
• Requires adaptive/antigen-specific
responses
• Long lived immunological memory
• Accelerated recall responses that rapidly
control the infection
Passive immunity involves
the transfer of preformed
antibodies
Active immunity gives rise to
long-term protection
Naturally acquired vs.
artificial immunity
LIVE VIRAL VACCINES
Are attenuated forms of the parental (virulent) virus.
Infection with the attenuated (vaccine) strain does not
cause disease but induces protective immunity.
Therefore, the vaccinee is is immunologically protected if
exposed to the virulent virus.
POTENTIAL PROBLEMS WITH LIVE VIRAL VACCINES:
• Risk of reversion to virulence
• Storage and transportation
• Unrecognized agents may contaminate cultures
INACTIVATED or “KILLED” VIRUS
VACCINES
• Examples:
•
•
•
•
Inactivated poliovirus vaccine
Influenza virus vaccine
Hepatitis A vaccine
Rabies vaccine
• Efficacy Issues:
• Must ensure complete inactivation
• Multiple vaccinations (boosters) may be necessary
• Non-replicating agents may be less effective at eliciting
immune responses
SUCESSFUL VACCINATIONS:
SMALLPOX ERADICATION
• Virology and disease aspects
–
–
–
–
No secondary hosts; only infects humans
No persistent infection
Subclinical infections are not spread
Easily diagnosed
• Immunology
– Infection confers long term immunity
– One stable serotype
– Vaccine is cheap and stable
• Social and political aspects
– Severe disease with high morbidity and mortality
– Eradication from developed countries demonstrated
feasibility
– Political willingness
VACCINOLOGY
•
•
•
•
Subunit Vaccines
Viral Vectors
DNA Vaccines
Peptide Vaccines
ANTIVIRAL CHEMOTHERAPY
Viruses are obligate intracellular parasites.
Therefore antiviral drugs must specifically target viral
functions without inhibiting essential host cell
processes
Viral Life Cycle Slide
Possible Targets for Antiviral
Chemotherapy
TARGET
PROTOTYPE DRUG
Receptor analogs/WINs
Amantadine
RNA-dependent RNA
polymerase inhibitors
AZT (zidovudine)
HIV Tat inhibitors
Ribavirin
Interferons
Protease inhibitors
Attachment
Uncoating
Primary viral RNA synthesis in
RNA viruses
Reverse Transcription
Regulation of RNA synthesis
Processing of RNA transcripts
Translation of viral mRNA
Protease processing/maturation
Replication of DNA viruses
Replication of RNA viruses Acyclovir
RNA-dependent RNA
polymerase inhibitors
Key Points I:
• Viruses are obligate intracellular parasites
– There are numerous methods and routes of
transmission
– They infect permissive host cells
– This is defines their TROPISUM
• Local vs. Systemic infections
– Primary vs. Secondary Viremia
• Outcomes/ Types of Infection
– Acute/ latent/ chronic/ transforming
Key Points II:
• Immune Responses to Viruses
– Innate (Interferon a/b; Macrophages; NK cells)
– Adaptive (B cells/ Abs; T cells/ CD4/CD8)
– Detrimental effects?
• Viral Strategies for Evading the Immune Response
–
–
–
–
–
–
“Hide” from the immune response
Downregulate gene expression
Antigenic variation (DRIFTS and SHIFTS)
Downregulation of cell surface molecules (MHC class I)
Cytokine analogues/ interference
Tolerance
Key Points III
• Infection Control
• PUBLIC HEALTH
• VACCINES
– Live- attenuated
– Inactivated- killed
– Advantages/ disadvantages
• ANTIVIRAL CHEMOTHERAPY
– Target a virus-specific process
– Avoid cellular toxicity