Download Long-term pathological consequences of prenatal infection: beyond

Am J Physiol Regul Integr Comp Physiol 309: R1–R12, 2015.
First published April 29, 2015; doi:10.1152/ajpregu.00087.2015.
Review
Long-term pathological consequences of prenatal infection: beyond brain
disorders
Marie A. Labouesse, Wolfgang Langhans, and Urs Meyer
Physiology and Behavior Laboratory, ETH Zurich, Switzerland
Submitted 6 March 2015; accepted in final form 21 April 2015
autism; cytokines; gut microbiota; maternal immune activation; metabolic syndrome; schizophrenia
PRENATAL EXPOSURE TO INFECTIOUS pathogens or inflammatory
stimuli is increasingly recognized to play an important etiological role in neuropsychiatric and neurological disorders with
neurodevelopmental components (15, 21, 93, 99, 100). Significant associations between prenatal infection during pregnancy
and increased disease risk in later life have been revealed for
various brain disorders, including schizophrenia (19), autism
(7, 117), bipolar disorder (22, 116), mental retardation (61),
and cerebral palsy (31, 50). Hence, prenatal exposure to immune challenges may be best viewed as a general vulnerability
factor for neurodevelopmental brain disorders rather than a
disease-specific risk factor (52, 100). In this sense, the adverse
effects induced by prenatal infection may reflect an early entry
into a deviant neurodevelopmental route, but the specificity of
subsequent disease or symptoms is likely to be influenced by
the genetic and environmental context in which the prenatal
infectious process occurs. This concept would, indeed, be
consistent with the emerging evidence suggesting that seemingly remote disorders, such as schizophrenia, autism, attention-deficit/hyperactivity disorder, and major depression share
considerable amounts of risk factors and brain dysfunctions
(23, 92, 138). The presence of shared genetic and environ-
Address for reprint requests and other correspondence: M. A. Labouesse,
Physiology and Behavior Lab., Schorenstrasse 16, 8603 Schwerzenbach,
Switzerland (e-mail: [email protected]).
http://www.ajpregu.org
mental risks among those illnesses has led to the proposal
that they might lie along a continuum of genetically and
environmentally induced neurodevelopmental causalities
(103, 113), wherein prenatal infection may be one of the
many factors that shape the eventual pathological outcomes.
While the importance of prenatal immunological adversities
has been widely acknowledged in the fields of developmental
neuropsychiatry and neurology, less attention has been paid to
the possibility that prenatal exposure to infection may also play
an etiological role beyond central nervous system (CNS) disorders. Hence, the possible long-term effects of prenatal infection on disorders that are not primarily associated with CNS
dysfunctions may be somewhat underestimated. This seems
surprising for various reasons. The prenatal period is not only
a highly sensitive period for early brain development (99), but
also for other biological systems that develop in utero, including the innate and adaptive immune systems (47, 70), the
cardiovascular system (46, 60), the renal system (55, 80),
adipose tissue (140), and skeletal bones and muscles (20, 68).
It is, in fact, rather unlikely that maternal infection during
pregnancy would specifically disrupt fetal brain development;
instead, it may more generally represent a developmental
stressor for the entire organism. The underlying assumption for
this hypothesis is that infection leads to the secretion and
circulation of various immune system-related factors in the
maternal host and fetal environment, which, in turn, are likely
0363-6119/15 Copyright © 2015 the American Physiological Society
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Labouesse MA, Langhans W, Meyer U. Long-term pathological consequences of prenatal infection: beyond brain disorders. Am J Physiol Regul
Integr Comp Physiol 309: R1–R12, 2015. First published April 29, 2015;
doi:10.1152/ajpregu.00087.2015.—Prenatal immunological adversities such as
maternal infection have been widely acknowledged to contribute to an increased
risk of neurodevelopmental brain disorders. In recent years, epidemiological and
experimental evidence has accumulated to suggest that prenatal exposure to
immune challenges can also negatively affect various physiological and metabolic
functions beyond those typically associated with primary defects in CNS development. These peripheral changes include excessive accumulation of adipose tissue
and increased body weight, impaired glycemic regulation and insulin resistance,
altered myeloid lineage development, increased gut permeability, hyperpurinergia,
and changes in microbiota composition. Experimental work in animal models
further suggests that at least some of these peripheral abnormalities could directly
contribute to CNS dysfunctions, so that normalization of peripheral pathologies
could lead to an amelioration of behavioral deficits. Hence, seemingly unrelated
central and peripheral effects of prenatal infection could represent interrelated
pathological entities that emerge in response to a common developmental stressor.
Targeting peripheral abnormalities may thus represent a valuable strategy to
improve the wide spectrum of behavioral abnormalities that can emerge in subjects
with prenatal infection histories.
Review
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PERIPHERAL EFFECTS OF PRENATAL INFECTION
Obesity and Metabolic Dysfunctions
Epidemiological investigations in humans and experimental
work in animals both emphasize a critical role of the early-life
environment in shaping postnatal metabolic functions. Stimulated by the seminal work of David Barker and colleagues, the
concept of “early-life priming of adult disease” is now widely
accepted for various adverse health outcomes (37). In the
context of obesity and metabolic disorders, this concept refers
to the phenomenon that exposure to a specific environmental
factor during early prenatal or perinatal periods can induce
lifelong changes in metabolic functions, thereby predisposing
the organism to excessive adiposity and associated pathophysiological conditions, including impaired glucose homeostasis,
insulin resistance, Type 2 diabetes, and cardiovascular disease
(81, 89).
One of the most noticeable early-life adversities precipitating such metabolic dysfunctions is maternal obesity during
pregnancy (54, 141). Indeed, a robust association between
prenatal maternal obesity and an enhanced risk for metabolic
disorder in the offspring has been established by a plethora of
human epidemiological studies and translational animal models (41, 77). Because obesity is accompanied by chronic
low-grade inflammation (105, 131), it has been suggested that
enhanced systemic and placental inflammation in obese mothers may represent one of the mediating factors underlying the
developmental disruption of metabolic functions in the offspring (121, 127). Only relatively recently, however, epidemiologists have begun to explore more directly whether discrete
maternal exposure to infectious or inflammatory stimuli is
similarly associated with increased risk for metabolic disorder
in the offspring. A first line of evidence supporting this hypothesis comes from a human epidemiological study that used
a cross-sectional cohort design, in which more than 17,000
male singletons were included (25). The findings from this
study suggested a 34% increased risk of obesity [defined on the
basis of a body mass index (BMI) of 30 kg/m2 or more] after
being born to a mother with infection during pregnancy (25).
Interestingly, a similar positive association has also been found
following childhood infections (25), suggesting that the developmental period for infection-induced changes in adiposity
extends to the early postnatal life.
Work in developmental rodent models further supports the
hypothesis of causal effects between maternal immune challenge during pregnancy and long-term metabolic dysfunctions
in the offspring. For example, it has been shown that maternal
treatment with the bacterial endotoxin LPS during midpregnancy in rats induces a wide spectrum of metabolic
disturbances in the adult offspring, including increases in
body weight and adipose tissue, hyperphagia, and insulin
resistance (111). These effects were sex-specific and
emerged in male but not female rats, indicating that male
offspring are more vulnerable than females in terms of
developing metabolic abnormalities following maternal endotoxemia during pregnancy. Findings from other rodent
models of maternal immune activation further suggest that
the association between prenatal immune challenge during
pregnancy and development of metabolic disturbances is not
dependent on the precise identity of the infectious or inflammatory pathogen. In fact, such metabolic effects can
even be induced by prenatal exposure to specific inflammatory cytokines (29). Moreover, long-term metabolic abnormalities have also been observed in mouse offspring of
mothers that were exposed to the viral mimetic polyriboinosinic-polyribocytidilic acid (polyI:C), a synthetic analog
of double-stranded RNA that induces a virus-like acute
phase response (93). In this virus-like immune activation
model, offspring of polyI:C-treated mouse dams were
shown to develop altered glycemic regulation and abnormal
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to affect peripheral organs and brain structures in the developing organism to the same extent.
Another reason why we should not ignore CNS-remote
effects of prenatal infection relates to the clinical observations
that individuals with major psychiatric disorders often display
signs of physiological and metabolic dysfunctions, including
insulin resistance, Type 2 diabetes, obesity, and cardiovascular
disease (90). Even though chronic psychopharmacotherapy
may facilitate or even induce such abnormalities (40, 139), it is
becoming increasingly evident that they cannot solely be accounted for by chronic drug exposure. Indeed, certain metabolic and physiological dysfunctions often occur (albeit in a
somewhat less severe form) in drug-naïve or minimally medicated first-episode patients with mental illnesses (63, 124, 143,
153). These findings have been taken as circumstantial evidence that at least some of the metabolic and pathophysiological comorbidities in major brain disorders may have a developmental origin and, thus, emerge prior to the onset of fullblown psychiatric illness.
Finally, neurodevelopmentally acquired brain abnormalities
in response to maternal infection may also facilitate the development of metabolic and physiological dysfunctions across the
postnatal life span. For example, the development of homeostatic brain regions, such as the hypothalamus, encompasses a
number of steps that begin early in fetal life and continue
postnatally (135). Infection-induced maldevelopment of such
brain regions could thus impair the homeostatic control of
various physiological functions, including food intake, renal
functions, and reproduction (81, 89).
Here, we review the existing evidence indicating that the
long-term pathological consequences of prenatal immune
challenges are not solely confined to primary CNS disorders. Instead, they extend more globally to other physiological and metabolic dysfunctions in peripheral systems. Relevant studies were identified and selected using PubMed.
All articles published before December 2014 were screened
for relevance and were searched using the following search
criteria (in alphabetical order) in various combinations:
“animal model,” “autism,” “bipolar disorder,” “body
weight,” “cytokines,” “diabetes,” “dopamine,” “epidemiology,” “food intake,” “glucose,” “gut,” “homeostasis,” “hypothalamus,” “immune activation,” “infection,” “inflammation,” “LPS,” “maternal,” “metabolism,” “metabolic syndrome,” “microbiota,” “microglia,” “obesity,” “poly(I:C),”
“pregnancy,” “prenatal,” and “schizophrenia”. In addition to
reviewing the available literature, we also provide a conceptual framework suggesting that several apparently unrelated central and peripheral effects of prenatal infection may
not represent separate pathological entities but could, in
fact, result from interrelated pathological mechanisms that
are engaged in response to a common developmental stressor.
Review
PERIPHERAL EFFECTS OF PRENATAL INFECTION
Peripheral (and Central) Inflammation
Various rodent models demonstrate that maternal exposure
to infectious or immune system-activating agents leads to robust
post-acute immune changes at the maternal-fetal interface, including the placenta, amniotic fluid, and fetal organism (2, 6, 96, 97,
151, 154). The nature and/or severity of these changes are influenced by various factors, most notably the identity and/or intensity
of the pathogen (51, 94), the gestational timing of exposure (97),
and the genetic background of the infected host (2, 96, 154).
Despite this, it seems that maternal exposure to distinct infectious
or immune system-activating agents leads to partially overlapping
immune responses in the fetal system. These overlapping effects
are mostly characterized by increased fetal expression of inflammatory factors, such as proinflammatory cytokines and
chemokines (5). It is believed that abnormal expression of
inflammatory factors in the fetal brain contribute to, or even
mediate, abnormal brain and behavioral development following prenatal exposure to infection (79, 136). Indeed, as reviewed extensively elsewhere (95, 102), acute inflammation
during early fetal brain development may negatively affect
ongoing neurodevelopmental processes, such as neuronal/glial
cell differentiation, proliferation, migration, and survival, and,
thus, predispose the developing offspring to long-term brain
and behavioral dysfunctions.
Since signs of subchronic systemic (and central) inflammation are often present in at least a subset of patients with
neurodevelopmental disorders (64, 86, 92, 101, 150), considerable research has been undertaken to address the question of
whether maternal exposure to infectious or inflammatory
agents may lead to persistent inflammatory changes in the
offspring postnatally. The evidence for this hypothesis is, at
best, equivocal. Some studies using rodent models of bacterial
or viral maternal immune challenge have reported a significant
upregulation of circulating inflammatory factors such as proinflammatory cytokines or chemokines in the juvenile or adult
offspring (17, 43, 69). Other studies using the same animal
models, however, failed to find clear signs of systemic inflammation in juvenile or adult offspring born to immunologically
challenged mothers (96, 157), or they even reported opposite
effects that were characterized by blunted systemic inflammatory
activity following prenatal infection (115).
Inconclusive data also exist with respect to central inflammation. In the CNS, microglia and astrocytes are the major
immunocompetent cells, which drive both the induction and
limitation of inflammatory processes (122). This is achieved
through the synthesis of proinflammatory and anti-inflammatory cytokines, upregulation, or downregulation of various cell
surface receptors, such as pathogen recognition receptors, cytokine receptors, and numerous receptors crucial for antigen
presentation. Enhanced microglia activation in brain parenchyma, along with increased central production of secreted
inflammatory factors, is often taken as a sign of ongoing
inflammation in the CNS (48). The possibility that prenatal
infection leads to chronic signs of brain inflammation has been
supported only by some studies in rats and mice (17, 69),
whereas other rodent studies failed to find evidence for such
neuroinflammatory processes extending into neonatal or adult
life (5, 43, 96, 119, 151, 157).
The inconsistency surrounding the long-term effects of prenatal infection on the persistence of inflammatory processes
across the postnatal life span may be explained by various
factors, most notably the severity and/or chronicity of the
infectious process targeting the maternal host. Indeed, it appears that more marked postnatal inflammatory changes are
seen following relatively severe forms of maternal immune
challenge, such as chronic exposure to immune system-activating agents throughout the entire gestational period (17). In
contrast, acute or subchronic prenatal exposure to immune
system-activating stimuli in mice and rats appears to be largely
devoid of systemic and central inflammatory effects persisting
into the juvenile or adult period (5, 43, 96, 119, 151, 157). The
latter may not seem surprising because inflammation is typically counteracted by homeostatic processes that mount antiinflammatory and/or immunosuppressive responses upon the
induction of inflammation (132), which, in turn, dampen and
finally resolve the post-acute fetal inflammatory responses to
maternal immune activation (91).
Still, the developing organism might sustain latent inflammatory abnormalities that may not become apparent until
reexposure to specific immunogens postnatally. In support of
this hypothesis, it has been shown that prenatal virus-like
immune activation in mice leads to a persistent decrease in the
number of regulatory T cells (Tregs) in the spleen and mesenteric lymph nodes (58). Besides other functions, Tregs can
potently suppress innate and adaptive immune responses, so
that a disruption of normal Tregs functions can lead to exacerbated inflammatory reactions (24). Such an exacerbation is
seen in mouse offspring born to immunologically challenged
mothers, which mount a potentiated proinflammatory T-cell
response to immunogenic T-cell stimulation (58).
Prenatal virus-like immune activation in mice has further
been shown to induce long-term changes in macrophage function that persist into adulthood. More specifically, bone marrow-derived macrophages of prenatally poly(I:C)-exposed
mice show an augmented proinflammatory cytokine response
to in vitro LPS stimulation alone, or in combination with
interferon (IFN)-␥ (112). The costimulation with LPS and IL-4
does not result in a similar proinflammatory cytokine signature
(112). Collectively, these results indicate that prenatal viruslike immune activation potentiates the polarization of macrophages toward an M1 phenotype, which, in turn, is typically
associated with larger production of proinflammatory cytokines, such as IL-12, at the expense of reduced production of
anti-inflammatory cytokines, such as IL-10 (85, 106). Thus, it
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ingestive behavior in adolescence and excess fat deposition
in adulthood (115). Similar results were obtained in a mouse
model, in which pregnant mice were infected with Ljungan
virus (LV), a virus that belongs to the Picornavirus family
and is virulent for laboratory rodents (126). Maternal LV
exposure in mice has been shown to predispose the offspring
to signs of Type 2 diabetes and obesity (110). These effects,
however, were particularly manifest in LV-exposed mice
that experienced additional stress during adolescence, suggesting that the severity of metabolic abnormalities following prenatal immune activation can be exacerbated by exposure to other environmental adversities, such as adolescent stress (110). These findings are particularly relevant for
the multifactorial etiology of obesity and Type 2 diabetes,
which are likely caused by a combination of environmental
(and genetic) factors (38, 81).
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Review
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PERIPHERAL EFFECTS OF PRENATAL INFECTION
Gastrointestinal Abnormalities and Dysbiosis
In recent years, there has been an increasing interest in the
relative potential of gastrointestinal (GI) functions to modulate
neuropsychological traits implicated in psychiatric disorders
(28, 87, 88). Epidemiological and clinical studies have repeatedly demonstrated a high comorbidity between GI inflammatory disorders and stress-related psychiatric symptoms, such as
anxiety or depressive behavior (28, 36). These findings have
been complemented by experimental studies in rodents showing that abnormal development of the gut microbiota leads to
neuroendocrine, neurochemical, and emotional abnormalities,
some of which are reminiscent of hormonal and behavioral
aberrations typically seen in depression and/or anxiety disorders. For example, ablation of the commensal GI microbiota in
germ-free mice or by chronic antimicrobial compounds can
lead to functional changes in the hypothalamus-pituitary-adrenal (HPA) axis and in the central dopaminergic, serotonergic,
and GABAergic neurotransmitter systems, and these effects
are further linked to the emergence of increased anxiety-like
behavior (11, 35).
Other clinical populations, for which GI abnormalities and
dysbiosis seem clinically relevant, comprise individuals suffering from neurodevelopmental psychiatric illnesses. Indeed, in
addition to the pathological symptoms traditionally attributed
to CNS dysfunctions, neurodevelopmental psychiatric illnesses, such as autism and schizophrenia, are also associated
with a number of GI dysfunctions. Such abnormalities include
chronic intestinal low-grade inflammation, increased intestinal
permeability (“leaky gut”), allergic reactions to dietary proteins, diarrhea, gastric dysmobility, and alterations in gut
microbiota (16, 26, 133, 136). By further undermining general
physical health and daily life quality, GI distress induces an
additional clinical burden to patients suffering from psychiatric
disorders (9, 53).
In view of the etiological contribution of prenatal infection
to neurodevelopmental diseases, experimental research has
begun to explore whether early-life immune challenges may be
a relevant environmental risk factor for the development of GI
abnormalities. In a seminal recent study, Hsiao et al. (58)
demonstrated that prenatal polyI:C-induced immune activation
in mice can indeed cause long-term defects in intestinal integrity and alterations in the composition of the commensal
microbiota. The former effect was evident by increased translocation of dextran across the intestinal epithelium and was
associated with decreased colonic expression of tight junction
components. Interestingly, signs of intestinal disintegrity in
polyI:C-exposed mouse offspring were already present by
the age of 3 wk, suggesting that these abnormalities are
established during early life. Furthermore, the colons from
prenatally infected mice displayed increased expression of
the inflammatory cytokine IL-6, which is in line with the
notion that increased gut permeability is commonly associated with altered immune responses in the GI tract (148).
Offspring of immunologically exposed mouse dams also
markedly differed from control offspring in terms of their
gut microbiota composition, and this difference was mostly
accounted for by differences in the relative abundance of
Clostridia and Bacteroidia classes (58).
The study by Hsiao et al. (58), which used a mouse model of
virus-like immune activation, is, thus far, the only one that
directly assessed the influence of prenatal immune challenge
on the development of GI abnormalities in the offspring.
Hence, it remains essentially unknown whether similar effects
can also be induced by prenatal exposure to other infectious or
inflammatory agents. It should be noted, however, that remarkable changes in the gut microbiota composition and associated
intestinal abnormalities have also been identified in another
experimental model of neurodevelopmental disease, namely
prenatal exposure to valproic acid (VPA) in mice (34). Similar
to the polyI:C model (83), the VPA model is frequently used to
induce autism-related brain and behavioral abnormalities in
experimental rodents (123). Thus, it appears that prenatal
exposure to distinct environmental factors does not only induce
overlapping neurobehavioral phenotypes, but further induce
similar changes in GI functions and microbiota. It remains
currently unknown whether the latter commonalities may be
explained by mutual pathogenic mechanisms, whereby neurodevelopmentally acquired abnormalities could increase the
vulnerability to GI pathology through mechanisms involving a
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seems that prenatal immune activation can prime the offspring’s peripheral immune system in such a way that it
mounts more excessive proinflammatory responses in the event
of postnatal pathogen (re-)exposures.
It should also be pointed out that prenatal immune activation can similarly lead to latent immune abnormalities in
the CNS. As reviewed in detail elsewhere (14, 50), numerous experimental studies in rodents show that immunological exposure in early (prenatal or neonatal) life can cause
the organism to mount differential (and often more vigorous) CNS inflammatory responses to subsequent immunological or nonimmunological challenges. For example, even
though prenatal virus-like immune activation per se does not
cause overt glial abnormalities and associated inflammatory
changes in the brain parenchyma of mouse offspring (5, 43,
157), signs of microglia overactivation and exacerbated
inflammatory cytokine secretion in CNS areas can be induced in these offspring when they are additionally exposed
to subchronic stress postnatally (44). This form of immune
sensitization or priming suggests that prenatal immune activation can markedly increase the vulnerability of the
offspring to brain immune changes in response to stress. A
similar microglia-priming effect by prenatal immune challenge has been demonstrated in a virus-like immune activation model, in which mouse offspring were subjected to
either prenatal poly(I:C) treatment alone, or in combination
with a second poly(I:C) treatment regimen in late adulthood
(69). In this model, mice exposed to both prenatal and
postnatal poly(I:C) treatment showed more extensive microglia activation and astrogliosis compared with either treatment alone (69).
Taken together, even though the long-term effects of prenatal immune activation on peripheral and central inflammatory
responses may not be apparent under basal conditions, they
may become so when the offspring are exposed to additional
environmental challenges, such as stress or acute infection
during the postnatal life. In addition, persistent inflammatory
abnormalities may develop more locally and may thus emerge
in specific peripheral organs. The latter possibility is discussed
in more detail in the subsequent section.
Review
PERIPHERAL EFFECTS OF PRENATAL INFECTION
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disruption of the normal top-down (CNS to GI tract) signaling.
This possibility is discussed in more detail below.
Do Peripheral Abnormalities Contribute to Neurobehavioral
Deficits Following Prenatal Infection?
Fig. 1. Graphical illustration of main top-down [central nervous system (CNS)
to periphery] and bottom-up (periphery to CNS) communication pathways and
summary of peripheral and central pathologies emerging following prenatal
infection. Top-down and bottom-up communication pathways are represented
by solid and dashed lines, respectively. CNS, central nervous system; CORT,
cortisol/corticosterone; NA, noradrenaline; Treg, regulatory T cells.
(58). On the basis of their subsequent findings showing that
prenatal virus-like immune challenge in mice leads to impaired GI
functions and dysbiosis, Hsiao et al. (59) went on to show that oral
treatment with the human commensal Bacteroides fragilis normalizes gut permeability and microbial composition and further
corrects autism-related behavioral deficits in mouse offspring born
to immunologically challenged mothers. Together, these findings
support the hypothesis that gut- and immune system-related peripheral abnormalities following prenatal infection have a direct
impact on CNS functions, so that normalization of the former
leads to beneficial effects on the latter.
A similar conclusion can be drawn from a recent investigation in mice demonstrating a link between prenatal virus-like
immune activation and the emergence of altered purine metabolism in plasma (108). Besides other metabolic changes, offspring of immunologically challenged mouse dams showed
marked signs of hyperpurinergia, a pathophysiological condition that is characterized by increased (plasma) levels of
purines. Importantly, Naviaux et al. (108) showed that an
antipurinergic therapy using acute administration of suramin
not only normalizes the peripheral metabolic abnormalities in
prenatally infected mice, but further corrects several of the
behavioral deficits typically observed in untreated offspring. In
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Even though the evidence for altered peripheral functions in
prenatally infected subjects is emerging, it remains largely
elusive whether these abnormalities functionally contribute to
the manifestation of neurobehavioral deficits. In other words,
do peripheral and central abnormalities, which can both be
precipitated by early-life adversities such as prenatal infection,
represent separate pathological entities? Or is there a pathological connection between the two, so that functional abnormalities in the former can lead to pathological changes in the
latter?
It is obvious that the latter scenario would require bottom-up
(periphery to CNS) and top-down (CNS to periphery) pathways that allow a bidirectional communication between the
brain and the peripheral systems. As extensively reviewed
elsewhere (12, 27, 28, 88), such pathways, indeed, exist and are
evolutionarily well conserved across species. In fact, this
bidirectional communication between the CNS and periphery
is pivotal for body homeostasis and adaptive responses to
changes in environmental conditions. Various peripheral
signals such as GI peptides, cytokines, neuroactive bacterial
metabolites, and adipose-derived factors can be relayed to the
CNS via multiple routes, including the vagal afferents and the
blood circulation (12, 27, 28, 88). The latter allows transport of
systemic signals into the CNS through specialized transport
systems embedded in the blood-brain barrier (BBB), or at sites
lacking a complete BBB, such as the circumventricular organs.
Afferent vagal nerve fibers are the main neuronal pathways
through which peripheral signals can be conveyed to the brain
(Fig. 1). Vagal afferent neurons synapse bilaterally on the
nucleus tractus solitarii, from where neuronal signals are transmitted to other brain stem nuclei and to various forebrain
structures, such as the hypothalamus, nucleus accumbens,
amygdala, and prefrontal cortex (12). On the other hand, the
periphery is connected with and modulated by the CNS
through neuronal efferent branches of the sympathetic and
parasympathetic nervous systems, which regulate visceral
functions, both at rest and in response to activating stimuli
(134). The periphery is further regulated by factors secreted by
various neuroendocrine systems, such as the HPA axis, which
has a central role in regulating many homeostatic processes,
particularly in response to stress-related stimuli (10).
In view of these elaborated bidirectional communication
pathways, it may not be surprising that interventions directed at
peripheral targets have the potential to ameliorate neurobehavioral deficits in offspring exposed to prenatal infection. A proof
of concept for this notion has recently been realized using
prenatal virus-like immune activation models in mice. In a first
study, Hsiao et al. (58) demonstrated that autism-like behavioral
abnormalities, which typically emerge in prenatally polyI:Cinfected mouse offspring, can be rescued by transplantation of
bone marrow derived from control offspring. This elegant
rescue experiment was conducted on the basis of the aforementioned findings showing that prenatal virus-like immune
activation in mice impairs development and functions of Tregs,
and further alters the differentiation of the myeloid cell lineage
Review
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PERIPHERAL EFFECTS OF PRENATAL INFECTION
Do Neurodevelopmental Deficits Contribute to Peripheral
Abnormalities Following Prenatal Infection?
While a direct influence of peripheral abnormalities to CNS
dysfunctions is supported by at least some animal studies, it
remains essentially unknown whether the opposite scenario
holds true as well. Hence, the role of neurodevelopmentally
acquired CNS dysfunctions in promoting peripheral abnormalities following prenatal infection still awaits thorough examination. In view of the elaborated top-down (CNS to periphery)
communication pathways (Fig. 1), however, it seems feasible
that abnormal functioning of discrete neuronal and neuroendocrine systems can, at least to some extent, facilitate the development and/or maintenance of peripheral abnormalities.
Perhaps one of the most obvious examples in this context
relates to the crucial role of the hypothalamus and interconnected structures in controlling food intake and energy balance
(104, 129). Given that maternal immune activation alters hypothalamic functions in rodent offspring (42, 78, 158), neurodevelopmentally acquired abnormalities in the hypothalamus
may contribute to the emergence of a hyperphagic phenotype
in offspring with prenatal infection (111, 115). An alternative
(but not mutually exclusive) mechanism underlying such
changes in food intake may be related to changes in the
mesocorticolimbic dopamine system. A plethora of investigations support a key role of dopamine in reward and incentive
values on the one hand, and in the associations between reward
and eating behavior on the other hand. These functional associations are highly complex and likely involve intricate interactions among homeostatic, hedonic, motivational, and associative processes (62, 104, 125). Prenatal immune activation in
rats and mice is well known to induce primary defects in early
dopaminergic development (91, 155) and to lead to long-term
dopaminergic abnormalities in the adult offspring (4, 98, 114,
155, 160). It seems, therefore, plausible that such dopaminergic
dysfunctions may be involved in the development of altered
food intake and energy balance, be it because of changes in
homeostatic, hedonic, motivational, and/or associative processes.
Another possible association that warrants careful examination in future studies is the potential impact of altered autonomic nervous system (ANS) functions in prenatally infected
animals. Initial evidence suggests that prenatal immune activation can cause hyperactivity of the sympathetic nervous
system, perhaps at the expense of diminished parasympathetic
nervous system functions. Hyperactivity of the sympathetic
nervous system typically leads to increased secretion of noradrenaline and corticosterone, both of which have been observed in mouse offspring that were exposed to prenatal immune challenge (115, 158). Prolonged secretion of these stressrelated factors can negatively influence GI physiology,
including gut motility, secretion, permeability, and composition of the gut microbiota (13, 67). Given that some of these GI
abnormalities have been shown to develop in mice exposed to
prenatal immune challenge (59), it would appear highly warranted to explore whether they may be causally related to a
hyperactivity of the sympathetic nervous system.
At the same time, diminished activity of the parasympathetic
branch of the ANS may contribute to the development of
altered inflammatory responses in the GI tract and other peripheral organs (120). Indeed, efferent vagal pathways originating from the dorsal motor nucleus of the vagus possess
anti-inflammatory activity by releasing ACh, which, in turn,
inhibits proinflammatory cytokine secretion by peripheral immune cells upon binding to ␣7 nicotinic receptors (118, 145).
This parasympathetic mechanism of neuronal anti-inflammatory signaling has been termed “the cholinergic antiinflammatory pathway” and seems to play an important role
in dampening peripheral inflammatory responses (118, 145).
Whether this pathway is altered by prenatal exposure to
infection still awaits direct examination, but it could provide
a contributing factor for the prenatal infection-induced disturbances in local inflammatory responses, including intestinal inflammation (59).
Possible Mechanisms Mediating the Effects of Maternal
Infection on the Offspring
The precise mechanisms responsible for mediating the pathological effects of maternal infection on the developing organism in utero remain to be determined. In fact, several plausible
mechanisms exist, whereby maternal infection can negatively
affect the normal development of peripheral (and central)
organs. As summarized in Fig. 2, the different pathological
mechanisms induced by infection may not be mutually exclusive, but may rather interact with each other to affect various
developmental processes that take place in prenatal life.
One prevalent hypothesis suggests that common immunological factors, in general, and inflammatory cytokines, in
particular, are key mediating factors changing developmental
trajectories in the offspring (4, 45, 79, 96, 102, 137). Inflammatory cytokines are typically induced during the acute phase
response to infection (146, 147) and may represent a major
developmental stressor for the organism (18, 57, 95). In the
event of maternal infection, an increase in fetal cytokine levels
may be caused by transplacental transfer of maternally pro-
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addition to immunological and gut-related factors (58, 59),
alterations in blood purine metabolism, thus, seem to be another peripheral pathology that readily contributes to the emergence of behavioral deficits following prenatal infection (108).
Thus far, it remains unknown whether other metabolic
disturbances that are induced by prenatal infection, including
alterations in glycemic regulation, insulin insensitivity, and
increased adiposity, may also directly influence behavioral
functions in subjects with a history of prenatal infection.
Hence, it remains to be determined whether normalization of
these metabolic abnormalities may exert beneficial effects on
behavioral deficits in this population. Furthermore, the precise
link between individual peripheral abnormalities also remains
elusive. For example, it is not known whether the excessive
accumulation of adipose tissue in offspring of infected mothers
may facilitate excessive proinflammatory signaling. Such a
link has been demonstrated in various models of obesity, but it
still awaits direct verification in models of prenatal immune
challenge. Given the emerging functional relationships between the gut microbiome and obesity and between the gut
microbiome and Type 2 diabetes (144), it would also seem
warranted to explore such possible connections in the context
of pathologies that are associated with prenatal exposure to
infection.
Review
PERIPHERAL EFFECTS OF PRENATAL INFECTION
duced cytokines (30, 159), by placental production of cytokines (6, 56, 128), or by increased fetal cytokine synthesis (97).
In addition to its effects on inflammatory cytokine secretion,
infection and the subsequent induction of inflammatory responses are also strongly associated with numerous other
pathophysiological effects, including oxidative stress. Oxidative stress is referred to as an imbalance between the production and elimination of reactive oxygen species (ROS), some of
which are highly cytotoxic and promote tissue injury (66).
Upon activation, innate immune cells secrete ROS and reactive
nitrogen species (RNS) as a central part of killing invading
pathogens (107). Production of ROS and RNS is, thus, an
important downstream mechanism of inflammation-mediated
immune responses. Several lines of evidence from rodent
models suggest that infection-induced increases in fetal ROS
and RNS levels may, indeed, be involved in changing development trajectories in the offspring (74, 75).
Besides its effects on oxidative stress systems, exposure to
infection and the subsequent cytokine-associated inflammatory
reactions further lead to the activation of the HPA axis by
stimulating the release of corticotropin-releasing factor from
the hypothalamus and of adrenocorticotropic hormone from the
pituitary gland; this results eventually in an increase of glucocorticoid levels in the peripheral bloodstream (49). The cytokine-mediated effects on glucocorticoid secretion may be of
special interest because it has been suggested that prenatal
physiological stress triggered by high glucocorticoid levels can
interfere with normal physiological and metabolic development (130, 156). Activation of the innate immune system (in
response to infection) also changes the maternal and fetal
availability of several micronutrients, including iron and zinc,
both of which are highly important for the normal development
of peripheral and central organs (3, 71, 72, 149). In the case of
iron, it is well established that infection leads to a temporary
depletion of iron in the infected host. This process is mediated
to a great extent by the proinflammatory cytokines IL-1␤ and
IL-6 (76, 109) and serves to reduce the availability of this
essential nutrient to the invading pathogens as part of the host’s
inherent defense system (65). As part of the acute-phase
response to infection, proinflammatory cytokines also trigger
the induction of the zinc-binding protein metallothionein (152).
During the course of pregnancy, this process leads to maternal
and fetal zinc deficiency, which has further been associated
with teratogenicity and abnormal developmental processes in
utero (33, 142).
In addition to its effects on micronutrient availability, maternal infection during pregnancy may also impair the fetal
supply for macronutrients. Indeed, it is well established that
peripheral cytokine elevation in response to infection induces a
set of behavioral and physiological changes collectively referred to as sickness behavior (32). Sickness behavior typically
includes fever, malaise, and reduced exploratory, and social
investigation, as well as decreased food and water intake,
accompanied usually by weight loss. The effects of immune
challenge on weight loss may be particularly relevant because
prenatal malnutrition has also been implicated as a risk factor
for various developmental disturbances (73, 84).
Finally, it should also be noted that at least part of the
changes to the microbiome that emerge following prenatal
infection (59) may have an early prenatal origin. The conventional view is that microbial colonization begins at birth when
the neonate is first exposed to the microbiome of the mother
and the surrounding environment (39, 82), implying furthermore that the fetal environment is sterile and, therefore, lacks
a microbiome before birth. This view has recently been challenged by findings showing that the human placenta is not
sterile but, in fact, is colonized with nonpathogenic commensal
microbiota (1). Perhaps even more important are the findings
suggesting that the microbial composition of the human placenta can be modified by maternal infection during pregnancy,
even if the infectious process takes place during the time of
conception or in early gestation (1). One important implication
from these recent findings is that modifications of the placental
microbiome, be it as a result of maternal infection or by other
environmental factors, can critically shape the development of
the offspring’s microbiome and, thus, predispose the developing organism to dysbiosis and other microbiome-associated
abnormalities.
Defining the Next Steps
Prenatal immunological adversities, such as maternal infection, have been widely acknowledged to contribute to an
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Fig. 2. Possible mechanisms mediating the pathological effects of maternal
infection on the developing organism in utero. Maternal infection during
pregnancy induces a number of pathophysiological responses in the maternal
host, including production of soluble immune factors, such as cytokines,
reactive oxygen species, and soluble endocrine factors, such as stress hormones. Some of these factors might cross the placental barrier and enter the
fetal environment, thereby causing fetal inflammation and oxidative stress.
Abnormal fetal expression of these factors might impair the normal development of peripheral and central organs by modifying the differentiation, proliferation, and/or migration of target cells. These processes may involve
alterations in gene expression via epigenetic modifications. Maternal infection
during pregnancy can further induce inflammatory response in the placenta and
cause placental insufficiency, which, in turn can cause fetal hypoxemia. In
addition, infection can cause (temporary) states of macronutrient and micronutrient deficiency, which limit the fetal availability of essential nutrients
necessary for normal fetal development and growth. Finally, maternal infection
during pregnancy can modify the microbial composition of the placenta, which
might alter the development of the offspring’s microbiome and thus predispose
the developing organism to dysbiosis and other microbiome-associated
abnormalities.
R7
Review
R8
PERIPHERAL EFFECTS OF PRENATAL INFECTION
Perspectives and Significance
Several recent epidemiological and animal studies suggest
that infection-related prenatal adversities can negatively affect
various physiological and metabolic functions beyond those
typically associated with primary defects in CNS development.
These include excessive accumulation of adipose tissue and
increased body weight, impaired glycemic regulation and insulin resistance, altered myeloid lineage development in favor
of proinflammatory signaling, increased gut permeability, and
changes in microbiota composition. The existing data suggest
that these peripheral abnormalities can directly contribute to
the emergence of CNS abnormalities, so that a normalization
of peripheral symptoms effectively alleviates behavioral deficits induced by prenatal infection. Thus, it follows that seemingly unrelated central and peripheral effects of prenatal infection may not represent separate pathological entities, but rather,
they may be considered as pieces of the same puzzle. In fact,
there might be a “vicious circle” involving constant pathological interactions between developmentally acquired brain abnormalities and peripheral dysfunctions, in which deficient
peripheral functions facilitate or maintain CNS abnormalities,
and vice versa. Thus, targeting peripheral abnormalities may
represent a valuable strategy to improve the multitude of
behavioral abnormalities that can emerge in subjects with
prenatal infectious histories.
ACKNOWLEDGMENTS
Related work by the authors has been supported by grants from the Swiss
National Science Foundation (310030_146217; to U. Meyer) and from ETH
Zurich, Switzerland (ETH Research Grant 25_13-2; to U. Meyer and W.
Langhans).
Present address: U. Meyer, Institute of Pharmacology and Toxicology,
University of Zürich-Vetsuisse, Zürich, 8057 Switzerland.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
Author contributions: M.A.L. and U.M. prepared figures; M.A.L. and U.M.
drafted manuscript; M.A.L., W.L., and U.M. edited and revised manuscript;
M.A.L., W.L., and U.M. approved final version of manuscript.
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