Transcript Consequences of virus infection in animal & other organism

Consequences of virus infection
in animal & other organism
• The consequences of a viral infection depend on
a number of viral and host factors that affect
pathogenesis.
• Viral infection was long thought to produce only
acute clinical disease but other host responses
are being increasingly recognized.
• These include asymptomatic infections,
induction of various cancers, chronic
progressive neurological disorders and possible
endocrine diseases.
Virulence
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Viral virulence, like bacterial virulence, is under polygenic control.
The susceptibility of a particular cell to viral infection depends mainly on the
presence of cellular receptors. Hence, cells resistant to a virus may be
susceptible to its extracted nucleic acid.
Cultivation may markedly alter the viral susceptibility of cells from that in the
original organ. For instance, polioviruses, which multiply in the nervous
tissue but not in the kidney of a living monkey, multiply well in culture cells
derived from the kidneys, since receptors develop in the cultivated kidneys
cells.
Many viruses are much more virulent in newborn animals than in adults
(e.g. coxsackieviruses, HSV or vice-verse e.g. polioviruses, hepatitis A).
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Genetic factors are also thought too play an important role in determining
the susceptibility of an animal to a virus.
Lytic infection
viral nucleic acid initiates destructive replication
cycle in which progeny virions are produced and
the host cell is destroyed
Epidemiology
• Acute infections are commonly associated with
epidemics (e.g. polio, influenza, measles, common cold)
• Main problem: by the time symptoms emerge, the host
has passed on the infection
• Difficult to control in large populations and environments
especially associated with people
• Effective antiviral drug therapy requires early
intervention, safe drugs with few side effect (not really
practical for acute infections).
• Cost: 90% of outpatient visits due to self-limiting acute
viral infections
Pathogenesis
 Destructive replication cycle
1. Attachment
– occurs as the virus uses its surface proteins to recognize and
bind to host cell surface structures called receptors and coreceptors
2. Penetration
– occurs as the virus enters the host cell
- enveloped viruses:
enter the host cell by one of two mechanisms:
» receptor-mediated endocytosis
» membrane fusion of their envelope and the cytoplasmic
membrane of the host cell, leading to formation of
endocytic vesicles containing the virus
- nonenveloped viruses:
are generally taken into the host cell by receptor-mediated
endocytosis
3. Uncoating
– occurs in a number of different ways, depending upon the virus,
its structure and its replication requirements, but in all cases it
releases the viral nucleic acid, which allows viral gene
expression to begin
- nonenveloped viruses:
» attachment to receptor(s) on the surface of the host cell
may trigger uncoating
» capsid proteins may be destabilized by the acidic
environment and/or digested by proteases inside endocytic
vesicles of the host cell
» capsid proteins may be digested by virion-encoded
proteases
- enveloped viruses:
» fusion with the host cell membrane uncoats or partially
uncoats enveloped viruses
» nucleocapsid(s) must then be removed by destabilization
and/or digestion
4. Synthesis
– depends upon viral gene expression to generate viral proteins
that are used as new virus structural components (capsomeres,
etc.)
– as enzymes participating in viral genome replication using viral
nucleic acid sequences as templates
- gene expression often occurs in more than one stage
(e.g., early and late gene expression)
- mechanisms mediating viral genome replication depend
upon factors such as whether the nucleic acid is DNA or
RNA, whether it is single- or double-stranded, and
whether or not it is segmented
5. Assembly
– occurs as viral proteins complex one another to form the capsid
(or its sub-components), then complex with viral nucleic acid
molecules to form icosahedral or helical nucleocapsids in the
case of:
- nonenveloped viruses:
these are stable mature infectious viral particles called
virions
- enveloped viruses:
these are unstable immature noninfectious
nucleocapsids (plus incorporation of viral protein
peplomers into the host cell membrane)
6. Release
– liberation of mature, infectious virions from the host cell in the
case of:
- nonenveloped viruses, release is generaly mediated by
viral lytic enzymes that lyse the host cell membranes
- enveloped viruses, maturation and release of virions is
typically mediated by membrane fusion events
(referred to as "budding") that enclose individual
nucleocapsids within an envelope comprised of host
cell membrane containing viral proteins (spikes or
peplomers) that were incorporated into it during the
synthesis phase of replication
Immunological response
• Most acute infections are rapidly resolved
• Limited by the intrinsic and innate immune responses
• Localization to the immediate site of infection,
Clearance by macrophages, NK cells,
polymorphonuclear cells, complement.
• Adaptive immune response provides memory against
subsequent infection.
• Virus-specific humoral and cellular responses
• If not quickly limited, acute infections are resolved by
host death (e.g. many haemorragic viruses, severely
immunocompromised patients)
Persistent infection
host cell remains alive and produces progeny
virions at a slow rate, but for a long time
Epidemiology
• Medical science has begun to control a number of virus
infections, many by drug treatment and/or immunization,
but persistent virus infections are largely uncontrolled.
• Diseases caused by persistent virus infections include:
acquired immune deficiency syndrome (AIDS), AIDSrelated complexes, chronic hepatitis, subacute
sclerosing panencephalitis (chronic measles
encephalitis), chronic papovavirus encephalitis
(progressive multifocal leukoencephalopathy),
spongioform encephalopathies (caused by prions),
several herpesvirus-induced diseases, and some
neoplasias.
• Successful medical treatment for persistent or chronic
virus infections is presently being developed. Attempts to
control latent virus reactivation have included vaccination
and treatment with interferon and various antiviral
compounds.
• Suppression of latent HSV, VZV and CMV reactivation
has been achieved in many immunocompromised
patients receiving acyclovir and/or ganciclovir treatment.
• Health education is an important component in
preventing the spread of infections that tend to persist.
Pathogenesis
 Immune modulation
• Many viruses that cause persistent infection avoid the
specific and nonspecific immune defenses in several
ways. Example:
a. Limitation of recognition molecules on infected cells:
> Restricted expression of viral antigens (e.g., HIV,
measles virus in subacute sclerosing panencephalitis).
> Antiviral antibody-induced internalization and
modulation of viral antigens (e.g., measles virus).
> Viral antigenic variation (e.g., HIV).
> Blocking antibody that prevents the binding of
neutralizing antibody (e.g., measles virus).
> Decreased expression of cell major histocompatibility complex
recognition molecules (e.g., CMV, adenoviruses).
> Restricted expression of the cell adhesion molecules LFA-3 and
ICAM-1 (e.g., EBV, CMV).
b. Altered lymphocyte and macrophage functions, including
modified production of cytokines and immunosuppression
(e.g., HIV-1, HIV-2, EBV).
c. Infection in immunologically privileged anatomic sites (e.g.,
HSV-1, HSV-2, VZV in the central nervous system).
d. Compromised nonspecific defenses (e.g., interferon).
 Modulation of viral gene expression
• Examples include down regulation of some viral genes
by viral or cellular regulatory gene products (e.g., HIV,
HPVs), specific latency-associated proteins (e.g., EBNA1) and possibly by synthesis of latency-associated
transcripts (e.g., HSV-1, HSV-2) and viral variants (e.g.,
HIV, measles).
Immunological response
• Autoimmune injury and other forms of cell damage may occur during
persistent infections.
• Budding virions and viral peptides associated with the cell
membrane change the antigenic characteristics of the cell so that
the immune system may recognize it as foreign.
• The cell then may be attacked by the humoral and cellular immune
systems of the host and may die, even if it was infected by a
noncytocidal virus.
Latent infection
there is a delay between infection of the host cell
and generation of progeny virions
Epidemiology
• Hepatitis B virus is prevalent in Southeast Asia and Africa. Tumors
are associated with primary infection at an early age, with viral
persistence and chronic infection. The virus can be sexually
transmitted particularly among homosexuals.
• Control of the development of hepatocellular carcinoma is being
tried by vaccination to control HBV infection. Safe and effective
vaccines have been available since 1982 but infant vaccination is
not yet universal in high risk countries. That universal vaccination
should be implemented by 1997 is a World Health Assembly
recommendation.
• African Burkitt's lymphoma (BL), the most frequent childhood tumor
in Africa, arises in areas where malaria is endemic and infection with
EBV occurs very early in life when the immune system may be
depressed by malaria or not yet mature.
• Preventive measures should be considered in individuals at risk of
serious disseminated varicella infection ie. the immunocompromised
and neonates.
• Immunocompromised individuals should be advised to avoid contact
with people with varicella or zoster. If contact has been made,
prophylaxis with passive immunization or antiviral chemotherapy
should be considered.
Pathogenesis
 Generation of cells that escape a cell-mediated immune
response
 Down regulation of MHC production in infected cells so
that they are not recognized and destroyed by T cells
 Infection of cells in immunoprivileged sites
such as the brain
Examples of latent infection include:
> Chronic
Congenital Rubella, CMV, EBV, hepatitis B, HIV
> Latent
HSV, VZV, adenovirus and some retroviral infections
> SSPE,
PML, Kuru, CJD, progressive rubella panencephalitis
Transformation
the viral nucleic acid triggers neoplastic
changes in the host cell which "immortalilze" it
and cause uncontrolled growth, which can
lead to tumors (cancer) in the host
Epidemiology
• Current data indicate that transformation of a cell
involves at least two components: first, the cell gains the
capacity for unlimited cell division (immortalization), and
second, the immortalized cells acquire the ability to
produce a tumor in an appropriate host.
• In vivo, the history of malignancies also suggests a
multiple process of cellular evolution, involving
cumulative genetic changes, selection of rare cells that
have the ability to invade, metastasize, and avoid
immune surveillance.
Pathogenesis
Benign tumor
• Noninvasive; tumor cells, often enclosed in a "capsule" of host
tissue, do not spread to other tissues
Malignant (metastatic) tumor
• Invasive; tumor cells spread to other tissues and proliferates there
Immunological response
• May cause formation of circulating antigen-antibody complexes
involving viral antigens.
• Complexes may deposit (e.g., in the glomeruli) and elicit
inflammation by activating the classical pathway of complement.
• The long-term association of the virus with specific target cells may
lead to altered function or responses; this type of mechanism is
thought to be responsible for the progressive neurologic disease
associated with slow virus infections