Download Viral Pathogenesis

VIROLOGIA
Viral Pathogenesis
•Viral Pathogenesis refers to the
series of events that occur during
viral infecrtion of a host.
•It is the sum of the effects on the
host of virus replication and of
immune response
Views of viral pathogenesis
POSSIBLE OUTCOMES OF VIRAL INFECTIONS
Acute Infection
Symptomatic infections
Persistent infection
•Chronic
•Latent
•Transformation
Inapparent infection
IS A DISEASE THE OUTCOME OF ALL VIRAL INFECTIONS?
The outcome of a viral infection depends from the
the characteristics of the virus-host interactions
and from the host defense response
Determinants of viral pathogenesis
Determinants of viral disease
IS A DISEASE THE OUTCOME OF ALL VIRAL INFECTIONS?
The hallmarks of virus-host interactions
Determinants of viral disease: nature of the
disease
•type of target tissues (replication sites);
•pathways of viral entry;
•viral spread to the replication sites;
•viral tropism;
•cells permissivity to virus replication;
•virulence of viral strain.
IS A DISEASE THE OUTCOME OF ALL VIRAL INFECTIONS?
The hallmarks of virus-host interactions
Determinants of viral disease: severity of the
disease
•cytopathogenic attitude of the virus;
•immunopathology;
•initial inoculum of the virus;
•compromised host;
•host genetic background;
•age.
IS A DISEASE THE OUTCOME OF ALL VIRAL INFECTIONS?
The hallmarks of virus-host interactions
Determinants of viral disease: severity
of the disease
The host immune conditions:
•competence of the immune system;
•previous exposure to the virus (immunity)
VIRAL PATHOGENESIS
The process by which viruses cause disease
•Viral entry
•Viral spread
•Tissue invasion
•Tropism
•Virus shedding and
transmission
•The host defense
•Disease
Viral pathogenesis: time course of typical infection
Sites of virus entry into the host
Different routes of viral entry into the host
Incubation periods of some common viral infections
Virus infection and spread into the host
PENETRATION
PRIMARY
REPLICATION
LOCALIZED INFECTION
PRIMARY
VIREMIA
TARGET TISSUES
influenza, enteric viruses
Sensistivity and permissivity
SECONDARY
REPLICATION
SECONDARY
VIREMIA
DISSEMINATE
INFECTION
exhantema viruses, polio
Entry, dissemination and shedding of blood-borne viruses
Infections can be
localized, or can
spread beyond the
initial site of
replication (a
disseminate
infection)
With many organs
involved the
infection becomes
systemic
Sites of virus entry in the respiratory tract
Enterovirus pathogenesis
Rabies pathogenesis
Varicella-zoster (VZV) infection and spread
VZV enters via conjunctiva and
upper respiratory tract
Replication occurs in regional
lymph nodes
Primary viremia via infected T cells
Replication in visceral organs (liver,
spleen, etc.)
Secondary viremia and subseqeunt
acute infection of skin -”chicken
pox” rash
Latency establish in sensory
ganglia of PNS
Reactivation results in “shingles”postherpetic neuralgia
Viral pathogenesis is the sum of the effects on
the host due to virus replication and the immune
response
• Direct effects of primary infection by cytolityc viruses
(e.g. virus-induced lysis of neurons in CNS by poliovirus)
• Indirect effects of noncytolytic viruses
(e.g. conseguence of the immune response)
•CD8+ T cell-mediated
•CD4+ T cell-mediated
Th1
Th2
•Antibody-mediated
•Immunosuppression
(HIV, HBV, Coxackievirus B)
(measle, HSV)
(RSV)
(HBV, rubella)
(HIV, CMV, measle, influenza)
Measles virus infection and spread
Kinetics of virus replication and immune responses
The kinetics of virus replication and the kinetics of the defensive response both affect the outcome
Slow localized spread
Intermediate spread
Fast disseminate spread
General patterns of infection
General patterns of infection
Acute infection followed by clearance of virus:
•productive infection
•viremia (circulating virus)
•clearance by immune system
•example: rhinovirus (common cold)
The course of typical acute infection
Some persistent viral infections of humans
Acute infection followed by latent infection and
periodic reactivation:
• initial productive infection with viremia
• viral persistence in non-infectious form
• intermittent reactivation with productive infection
• example: herpes simplex virus type 1 (HSV-1)
HSV-1 latency and reactivation
1.
2.
3.
4.
5.
6.
7.
Productive infection of epithelial cells
Virus infects sensory neurons
Virus travels to sensory ganglion by neuronal retrograde transport
Virus establishes latent infection in sensory ganglion
Limited expression of viral genes, latency associated transcripts (LATs),
viral genome replicates in episomal state
Virus may be reactivated by changes in physiological status of the
neuron
(neuron damage, immunosuppression, hormonal changes, stress, UV)
Changes lead to activation of viral gene expression and productive
infection
HSV-1 primary infection of a sensory ganglion
HSV-1 latency
and reactivation
Epstein-Barr virus primary and persistent infection
Acute infection followed by chronic infection:
•initial productive infection with viremia
•virus not cleared completely by immune system
•continuous, low-level productive infection
•may be "smoldering" infection (productive infection
by small fraction of cells)
•example: human immunodeficiency viruses (HIV)
HIV
•initial productive infection of permissive cells
•viremia
•apparent latent infection
•evidence for smoldering infection of population of permissive cells
•antigenic variants produced during time course of infection:
> 109 new cells infected each day; every possible point mutation occurs between
104 and 105 times per day in an infected individual
Slow, chronic infection
•seen only with unconventional infectious agents scrapie,
bovine spongiform encephalopathy (mad cow disease)
•continuous and slowing increasing production of
infectious agent with time.
MECHANISMS OF VIRAL PATHOGENESIS
CELLULAR PATHOGENESIS
HOST IMMUNE RESPONSE
EPIDEMIOLOGY, PREVENTION AND CONTROL
MECHANISMS OF VIRAL PATHOGENESIS
CELLULAR PATHOGENESIS
HOST IMMUNE RESPONSE
EPIDEMIOLOGY, PREVENTION AND CONTROL
Cellular pathogenesis: patterns of infection
Type
Viral production
•Abortive
•Cytolytic
•Persistent
Chronic
Latent
Transforming
DNA viruses
RNA viruses
Cell fate
+
death
+
-
senescence
-
+
immort./transfor.
immort./transfor.
MECHANISMS OF CELLULAR PATOGENESIS
Direct effects of cytolityc viruses
• Cytopathic effect
• Inclusion bodies
• Apoptosis
• Dysregulation of cell physiology
Indirect effects of non-cytolytic viruses
• Host immune response
MECHANISMS OF CELLULAR PATOGENESIS
Cytopathic effect(s):
Virus(es)
• Inibition of host protein synthesis
polio, herpes, toga, pox
• Host chromosome margination and DNA
herpes
degradation
• Nuclear shrinking
picorna
• Proliferation of nuclear membrane
herpes
• Cell membrane alterations
enveloped viruses
• Vacuoles in the cytoplasm
papova
• Syncytia (cell fusion)
paramyxo, herpes, HIV
• Cell Rounding up and detachment
herpes, rabdo, adeno, picorna
Inclusion bodies:
•
•
•
•
•
Intranuclear basophils
adeno
Virion in the cytoplasm (Negri bodies)
rabdo
“Factories” in the cytoplasm (Guarnieri bodies) pox
“Owl eyes” in the nucleus
CMV
Perinuclear acidophils
reo
Cytopathic Effects: an overview
HSV-1
Syncitia formation
RSV
Measle virus
Inclusion bodies formation
Reovirus replicate in the cytoplasm and generate inclusion
bodies containing viral proteins stained by eosin
Mechanisms of viral
transformation and
oncogenesis
1
2
MECHANISMS OF VIRAL PATHOGENESIS
CELLULAR PATHOGENESIS
HOST IMMUNE RESPONSE
EPIDEMIOLOGY, PREVENTION AND CONTROL
HOST DEFENSES AGAINST VIRAL INFECTIONS
1. Physical barriers
2. Chemical barriers
3. Intrinsic cellular defenses
4. Innate soluble immune response: cytokines,
inflammation, fever, complement
5. Innate cellular immune response: DC, macrophages
6. Adaptive soluble immune response: antibodies
7. Adaptive cellular immune response: NK, CTL
Integration of intrinsic defense with the innate and
adaptive immune response
Intrinsic defense
responses
Apoptosis as a defense against viral infection
PATHOGENESIS OF A VIRAL DISEASE
The kinetics of host defense mechanisms
Immune reactions during the response to viral
infections that can cause host cell damage and disease
• Interferons and lymphokines: fever, headache,malaise.
• Delayed-Type
Hypersensitivity,
Complement
fixation, Immunocomplexes: cell damage and local
inflammatory responses.
• Inflammation due to the cell-mediated response:
severe tissue damages in adults.
• Immunocomplexes accumulation in the blood and
kidney: glomerulonephritis.
MECHANISMS OF VIRAL PATHOGENESIS
CELLULAR PATHOGENESIS
HOST IMMUNE RESPONSE
EPIDEMIOLOGY, PREVENTION AND CONTROL
EPIDEMIOLOGY OF VIRAL DISEASES
The study of the occurrence, distribution and control of diseases
• Prevalence: the proportion or percentage of individuals in the
population having a disease.
• Incidence: the total number of cases of disease in a population.
• Morbidity: incidence of illness in a population.
• Mortality: incidence of death in a population.
EPIDEMIOLOGY OF VIRAL DISEASES
The study of the occurrence, distribution and control of diseases
• Outbreak: the occurrence of a large number of cases of a
disease in a new site and in a short period of time (HAV).
• Endemic: disease constantly present, usually in low numbers.
• Epidemic: the occurrence of a disease in unusually high
numbers due to the introduction of new viral strain in a naive
population (Influenza).
• Pandemic: a worldwide epidemic due to the introduction of a
new virus (HIV, SARS, Influenza).
EPIDEMIOLOGY OF VIRAL DISEASES
Classification of disease by incidence
EPIDEMIOLOGY OF VIRAL DISEASES
The spread of the Asian influenza pandemic of 1957
EPIDEMIOLOGY OF VIRAL DISEASES
Recent outbreaks of emerging and reemerging infectious diseases
EPIDEMIOLOGY OF VIRAL DISEASES
Mechanisms of viral transmission:
•aerosol, infected things, direct contact, sexual contact, transplant,
blood-transfusion, zoonosis.
Factors influencing viral transmission
•Environmental persistence of virions;
•Viral replication in body fluids
Risk factors
•Age, health, immune status, work, travels, life style
Populations characteristics
•Percentage of susceptible serum-negative individuals
Geography/Season
Prevention and control
•Quarantine, vector elimination, immunization (natural infection,
vaccination), antiviral therapy
Viral infections are transmitted among hosts in specific ways
Acute viral infections with
seasonal variation in
incidence
Effect of humidity on transmission of influenza virus
EPIDEMIOLOGY OF VIRAL DISEASES
Prevention and control
Quarantine
Public health measures
•Directed against the reservoirs (domestic animals,
wild animal, insect, humans)
•Directed against transmission (food, water, air)
•Education (STDs)
Immunization
•Natural infection
•Vaccination
Antiviral therapy
EPIDEMIOLOGY OF VIRAL DISEASES
Prevention and control
Vaccines:
the proven best defense
against viruses
Antiviral drugs:
small molecules that block
virus replication