inflammation that promotes cellular adap-
tation to stress caused by the unfolded
protein response but is detrimental in
the context of bacterial inflammation
(Figure 1).
The study provided by Wang et al.
provides important mechanistic insight
as to how systemic metabolism influences
tissue susceptibility to damage during
inflammation and infection. In future
studies, it will be important to determine
in what tissues type I IFN signaling
is occurring to induce lethality. It is
also interesting to explore why different
regions of the brain respond differently to
bacterial and viral inflammation and
to identify the properties of neurons that
define their metabolic requirements and
susceptibility to damage in the context of
different inflammatory challenges. Finally,
it will beimportanttounderstand howacti-
vation of different Toll-like receptors leads
to very different cellular stresses.
It is worth noting that most studies
examining how anorexia influences host
survival, including the one by Wang
et al., rely on systemic inflammation
models or infection models in which
pathogen transmission is not considered.
However, understanding how anorexia
influences host defense strategies is
only half of the host-pathogen equation.
Energetic demands of pathogens are
dependent in large part on food intake
of their hosts, and any benefits afforded
by the anorexic response are also
dependent on how the fasted state influ-
ences pathogen behavior. Thus, future
work is warranted to assess how nutri-
tional status of the host and sickness-
induced anorexia regulates pathogen
virulence and transmission. It is also
important to understand the mechanisms
that microbes have evolved to manipu-
late anorexia and other sickness be-
haviors to promote their fitness. In infec-
tion settings in which anorexia results in
a negative impact on pathogen fitness,
for example, by promoting host resistance
mechanisms or inhibiting pathogen trans-
mission, one would predict that anorexia
could drive the selection of antagonistic
traits in pathogen populations that inhibit
infection-induced anorexia. By contrast,
in settings where anorexia promotes dis-
ease tolerance, it is intriguing to ask
whether, and if so how, microbes may
evolve traits to promote the anorexic
response. Insights along these lines could
be valuable for guiding nutritional supple-
mentation for disease management in
clinical settings.ACKNOWLEDGMENTSJ.S.A. is supported by an NIH grant
R01AI114929, the Nomis Foundation, the Searle
Scholar Foundation, the Ray Thomas Edward
Foundation, a Crohn’s and Colitis Foundation
Senior Research Award, and a DARPA Young
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