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Viruses can only survive by entering and parasitizing the cells
of a host. Because viruses cannot live independently of their interaction
with the parasitized host cell, all viruses have evolved strategies
for coexisting with cells, while these cells continue to carry out
physiologic functions as part of specific tissues or organs. It
is the complex interplay between viral and host properties that
determines the relationship that the virus will experience with
its host in vivo, whether resulting in disease
or not. The interplay between viral and host features thus determines
the pathogenesis of infection.
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Pathogenesis has generally been conceptualized as the series
of sequential steps starting with entry of the virus into host cells,
and progressing through survival of the virus and dissemination
of the virus in the host, to shedding of the virus from the host
to spread to new individuals where the virus continues its life
cycle. In the animal host, every virus must overcome a series of
defenses in order to enter, disseminate, and localize in the ideal
target tissue; replicate; and shed to infect new hosts. At each
stage, the host possesses specific mechanisms to inhibit the survival
of the virus, and the virus has evolved ways to counteract these
mechanisms. Some of these strategies for evading host defenses are
common to different viruses. Considering viral pathogenesis in this way
as the stepwise unfolding of events within the host is useful and
simple because thus far we know far more in most cases about the
virus itself than we do about the host side of the complex interplay.
When applying this model of viral pathogenesis, however, often the
steps may not occur sequentially, but rather several steps may be
occurring at the same time, or several alternate pathways may be
taken simultaneously.
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As new understanding of the host contributions to viral pathogenesis
emerges, the impact that an individual's genetic makeup has on susceptibility
to infectious disease has become clear. In fact, recent data suggest
that an error in a single gene is enough to dramatically alter an individual's
susceptibility to viral infections.1 It is becoming
apparent that pathogenesis should likely, in the future, be conceptualized
as a balance between the viral agent and the host’s immunologic
and genetic makeup.
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Genetic Susceptibility to
Infection
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For respiratory syncytial virus (RSV), several abnormal underlying
conditions that predispose to severe forms of disease have been
enumerated, and include prematurity, preexisting lung disease, and
various forms of immunodeficiency. However, it is not yet known
why some apparently normal infants and children proceed from initial
infection to severe lower respiratory tract disease, whereas others
experience a relatively mild, self-limited illness. Recent evidence
now points to a major role for genetic susceptibility. Certain alleles
of IL-4,10 and of the IL-4 receptor,11 are
associated with more severe disease, and promoter variants of IL-10,
IL-9, and TNF-α genes likely also influence disease
severity.12 Variations ...