INFECTION AND IMMUNITY, Apr. 2006, p. 1999–2006
4
0019-9567/06/$08.00⫹0 doi:10.1128/IAI.74.4.1999–2006.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
MINIREVIEW
Neonatal Innate Immunity to Infectious Agents
László Maródi*
Department of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
Host defenses to microbial invasion include the phylogeneti-
cally older but rapidly developing antigen-independent or in-
nate immunity and the much more slowly developing specific
or adaptive immunity (2, 35, 82, 91). Innate immune responses
are triggered by bacteria, viruses, protozoa, and fungi, as non-
self, and involve nonspecific activation of neutrophils, mono-
cytes and macrophages, dendritic cells (DCs), natural killer
(NK) cells, and complement. The importance of innate immu-
nity in defense against mycobacteria is illustrated by the ob-
servation that patients with T-cell-negative, B-cell-negative,
and NK cell-positive severe combined immunodeficiency
(SCID) may survive inadvertent vaccination with bacillus
Calmette-Guérin vaccine (64).
Phagocytosis as a mechanism of innate immune defense has
served as the classical model for studying host-parasite inter-
actions, and significant progress has been made toward under-
standing the molecular mechanisms of phagocytic uptake and
microbial killing (19, 25, 54, 57, 59). Recently, Toll-like recep-
tors (TLRs) have emerged as central points of innate immunity
(82, 91). TLRs represent a conserved family of immune recep-
tor sensing molecules on a wide variety of pathogens. These
receptors recognize pathogen-associated molecular patterns,
which results in activation of NF-␬B and other transcription
factors including interferon (IFN) regulatory factors. TLRs are
expressed on the surface of monocytes, macrophages, DCs,
and epithelial cells or in the cytoplasm of cells from different
tissues. Other immune receptors involved in innate immune
responses are the macrophage mannose receptor (MR) and
dectin-1 (25, 93). Ligand binding to innate receptors generates
intracellular signals, initiates gene activation, and enhances the
release of cytokines and chemokines at the site of immune
activation. Chemokines recruit innate immune effector cells
such as granulocytes, monocytes, macrophages, and NK cells
(32, 63, 65). An important humoral component of innate im-
munity is the complement system, which can be activated
through the alternative and lectin pathways, in addition to the
classical pathway, leading to antibody-independent opsoniza-
tion and opsonophagocytosis (55, 75).
Innate immunity is ontogenetically older than adaptive im-
munity, but innate recognition of pathogens is the first step in
inducing adaptive immunity (35). In vertebrates, innate and
adaptive immunity are overlapping and intervening. One major
difference in the biology of the two systems is that several
* Corresponding author. Mailing address: Department of Infectious
and Pediatric Immunology, Medical and Health Science Center, Univer-
sity of Debrecen, Nagyerdei Krt. 98, H-4012 Debrecen, Hungary. Phone:
36 52 416 841. Fax: 36 52 430 323. E-mail: lmarodi@jaguar.dote.hu.
1999
Vol. 74, No.
responses for innate immune recognition are encoded in the
germ line DNA and, in contrast to adaptive immune responses,
do not require gene rearrangement (35).
NEONATAL INNATE IMMUNITY
Human neonates and young infants are more vulnerable
to infectious agents than older children and adults and are
especially susceptible to infections with intracellular patho-
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gens. Some of the pathogens causing infections in utero, intra-
partum, and postpartum evoke fetal and neonatal innate im-
mune responses. These agents include group B streptococci
(GBS), Escherichia coli, Listeria monocytogenes, herpes simplex
virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus
(EBV), varicella-zoster virus (VZV), respiratory syncytial virus
(RSV), Toxoplasma gondii, and Candida species. Innate immu-
nity against these pathogens represents the critical first-line
barrier of host defenses, as newborns have a naı̈ve adaptive
immune system. The past decade has brought great strides in
our understanding of innate immune mechanisms in humans.
An increasing body of evidence suggests that neonatal innate
responses may not be fully developed, allowing early dissemi-
nation of infections. This review describes recent advances and
current understanding of innate neonatal immunity to infec-
tious agents that are thought to be responsible for significant
morbidity and mortality in newborns. Neonatal infection by
sexually transmitted disease pathogens (Treponema pallidum,
Neisseria gonorrheae, and Chlamydia trachomatis), human im-
munodeficiency virus (HIV), and hepatitis viruses will not be
discussed here. A better understanding of molecular mecha-
nisms that underlie neonatal immune functions may improve
our ability to prevent and treat neonatal infections.
INNATE RESPONSES TO NEONATAL PATHOGENS
GBS. GBS is the foremost cause of neonatal bacterial infec-
tions, and mortality of invasive GBS disease in newborns re-
mains high despite advances in intensive care and susceptibility
of the pathogen to penicillin and gentamicin (16, 78). The lack
of pathogen-specific maternal antibodies to the capsular poly-
saccharide antigen was supposed to contribute to susceptibility
and the severe course of disease in newborns. Accordingly, it
was believed that effective vaccination would be a way to re-
duce the incidence of GBS disease over the long term. In a
study including 321 healthy term newborns, immunoglobulin G
(IgG) antibodies against capsular polysaccharides of GBS se-
rotypes Ia, II, and III were present in 98 to 100% of cord sera
(10). However, the concentrations of IgG antibodies were of-
2000 MINIREVIEW
ten low and might not have been sufficient for protection.
Naturally occurring IgG antibodies with the capacity to opson-
ize GBS type III in a complement-dependent manner may also
play a role in host defense against these pathogens (22).
Neutrophils are the predominant mobile phagocytes of cir-
culating blood and may contribute to killing of GBS even more
than mononuclear phagocytes do. Importantly, exposure to
recombinant human IFN-␥ was found to activate cord blood
neutrophils and to result in enhanced chemotaxis and in-
creased concentrations of free intracellular calcium (31).
These data suggest that IFN-␥ may enhance the newborns’
own host defense by activating neutrophils.
Monocytes and macrophages have a rich diversity of cell
surface receptors complementing the diversity of microbial
molecules that they are likely to encounter, often in the context
of soluble opsonins such as complement and antibodies. Ear-
lier studies showed that the capacity of cord blood monocytes
to kill serum-opsonized GBS type III was decreased compared
to the capacity of adult blood monocytes (56). Interactions
between serum-opsonized GBS and monocyte-derived macro-
phages isolated from cord blood were also studied by using
resident and cytokine-activated cells (53). These results
showed that resident cord and adult macrophages efficiently
phagocytosed serum-opsonized GBS, but the ingested bacteria
survived inside the cells. Bacterial killing by cord macrophages
was augmented by granulocyte-macrophage colony-stimulating
factor but not by IFN-␥, suggesting differential modulation of
bacterial killing by these cytokines. Survival of GBS in neonatal
macrophages provides an additional explanation to the severity
of GBS disease in early life.
GBS types Ia and III may impair microbicidal systems in
murine macrophages by inhibiting protein kinase C-dependent
signal transduction pathways (17). Alternatively, macrophages
may fail to kill GBS unless they are activated. After phago-
cytosis, these cells may become permissive for bacterial repli-
cation. Therefore, ingestion by macrophages of opsonized
GBS may not only enhance but also interfere with elimination
of these bacteria at the site of tissue infection.
GBS vigorously activates inflammatory cytokine responses
by innate immune cells (36). Impaired interleukin-12 (IL-12)
production by GBS-exposed mononuclear phagocytes has re-
cently been proposed to be linked to IFN-␥ deficiency in new-
borns. GBS-stimulated mRNA accumulation and protein se-
cretion of both IFN-␥ and IL-12 in mononuclear cells from
cord and adult blood were studied (36). By using reverse trans-
criptase PCR and quantitative densitometry assays, the kinet-
ics of GBS-stimulated accumulation of IFN-␥ mRNA and
IL-12 mRNA were compared in cord and adult cells. After 12
to 18 h of incubation, significantly decreased mRNA accumu-
lation for both IFN-␥ and IL-12 was detected in cord cells
compared to adults. The concentrations of IFN-␥ and IL-12 in
suspensions of GBS-exposed cord mononuclear cells were also
significantly lower than in adults at 12 and 18 h. These data
suggest that, in addition to lymphocyte immaturity, IFN-␥ de-
ficiency in neonates may be linked to decreased production of
IL-12 by cord mononuclear phagocytes, at least when these
cells are stimulated with GBS. This observation also suggests
that strategies to enhance neonatal host defense against GBS
may include administration of IL-12.
INFECT. IMMUN.
The capsule of GBS is well characterized as one of the
virulence factors of streptococci. The capsule protects GBS
from opsonization by C3 through inhibition of the alternative
complement pathway in the absence of type-specific antibodies
(76). In addition, streptococcal proteins localized to the sur-
face of bacteria may bind complement factor H, retaining its
ability to down-regulate complement activation (6). Recently,
a surface-localized protease, CspA, that may play an important
role in GBS pathogenesis as an antiphagocytic surface factor
was described (28). CspA was found to be required for GBS
cleavage of human fibrinogen. GBS mutants that failed to
express cspA, the gene coding for CspA, displayed a signifi-
cantly decreased virulence in a neonatal rat model of GBS
infection and an increased sensitivity to opsonophagocytic kill-
ing. Further characterization of the expression and function of
surface-localized GBS proteins and enzymes will help us to
understand better how GBS that evade the host innate im-
mune response cause severe infections in newborns.
E. coli. E. coli is one of the leading gram-negative bacteria
that cause neonatal meningitis and sepsis (84). The mortality
rate and the neurological squeal remain high despite advances
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in antimicrobial therapy. Intracellular survival of E. coli rep-
resents one important pathogenicity mechanism. E. coli K1,
which causes meningitis in neonates, is able to enter and sur-
vive in human macrophages and peripheral blood monocytes
(85). Outer membrane protein A (OmpA) expression on the
surface of bacteria plays an important role in binding to and
phagocytosis by macrophages in the absence of opsonization.
E. coli expressing OmpA is able to bind the classical comple-
ment fluid-phase regulator C4b-binding protein to avoid depo-
sition of C3 and C5, subsequent phagocytosis by granulocytes,
and activation of the membrane attack complex (69). In addi-
tion, IgG does not bind efficiently to the surface of E. coli K1,
allowing the bacteria to avoid recognition via the Fc␥ receptors
of granulocytes. Deficiency of the alternative complement
pathway in cord blood contributes further to the opsonic defect
in neonates against E. coli (55). Under such conditions, entry
and survival within macrophages could play an important role
in the development of bacteremia and the course of meningeal
infection by E. coli (85).
Neonatal innate immune cells are characterized by de-
creased responses to pathogen-derived or physiologic stimuli
like lipopolysaccharide (LPS) and IFN-␥, respectively (44,
106). LPS, the primary constituent of E. coli and other gram-
negative bacteria, induces inflammation by binding to the
TLR4/MD2/CD14 complex on macrophages (35). Recent re-
search has shown normal expression of both TLR-4 and CD14
molecules on cord blood mononuclear cells but decreased
TLR-4-mediated signaling and ligand-induced tumor necrosis
factor ␣ (TNF-␣) release by these cells exposed to LPS (44,
106). These data suggest that the risk of overwhelming infec-
tion by E. coli in human neonates may be related to impaired
TLR-4-mediated responses by macrophages, in addition to
decreased opsonophagocytosis. Other authors found that neo-
natal mononuclear cells produce an enhanced amount of
TNF-␣ in response to LPS or GBS (102). These findings are in
concert with the enhanced sensitivity of neonates to TNF-
induced shock.
Listeria. Listeria infection in humans occurs most commonly
in newborns and in immunosuppressed children and adults
VOL. 74, 2006
(45). Perinatal infections caused principally by L. monocyto-
genes are usually secondary to maternal infection or coloniza-
tion. Macrophage activation is critically important for an effi-
cient killing of Listeria, and macrophage activation in vivo by
IFN-␥ is a sine qua non for protection (9, 46). The effectiveness
of innate immunity in host defense against Listeria has been
exemplified by studies using SCID mice that lack both T-cell
and B-cell immunity. These mice were remarkably resistant to
infection with L. monocytogenes due to a rapid neutrophil
response followed by activation of macrophages and were able
to control infection for several days (18). However, listeriosis
in mice with an SCID mutation results in a chronic infection
characterized by abundant granulomas, microabscesses, and
neutrophil infiltrates occurring mostly in the liver (11). There-
fore, even though the innate immunity is effective to provide
protection, an adequate immune response, i.e., clearance of
bacteria, granuloma formation with lymphocytes, and disap-
pearance of microabscesses, requires specific immunity. Adop-
tive transfer studies showed a decisive role of CD4⫹ and CD8⫹
T cells in augmenting innate antibacterial host defenses and
ensuring long-term survival of Listeria-infected adult mice (11).
The capacity of CpG oligodeoxynucleotides (ODN) to stim-
ulate protective immune responses to Listeria was recently
studied in newborn mice (34). These studies showed that DCs,
macrophages, and B cells from 3-day-old mice responded to
CpG stimulation by secreting IFN-␥, IL-12, and TNF-␣. In
addition, spleen cells from CpG-treated newborn mice pro-
duced large amounts of cytokines and nitric oxide when ex-
posed to Listeria in vitro. In concert with these findings, new-
borns treated with CpG ODN were protected from lethal
Listeria challenge (34). These data suggest that cellular ele-
ments of the neonatal immune system, similar to those of adult
mice, may respond to stimulation by CpG ODN, thereby re-
ducing host susceptibility to infectious pathogens.
The hematopoietic growth factor Flt3 ligand (FL) was found to
induce a ⬎100-fold increase in the innate resistance to Listeria
infection in neonatal mice (95). In particular, FL induced in-
creases in DC numbers as well as IL-12 production by these cells
(96). The increased IL-12 production may be crucial in defense
against Listeria in vivo through stimulating IFN-␥ release by T
cells and NK cells and most likely explains the increased survival
of FL-treated neonatal mice. Although these studies did not
clearly define differential responses to FL by adult versus neonatal
mice, they indicate that newborn mice treated with this hemato-
poietic growth factor have a distinct advantage over untreated
littermates to control Listeria infections.
TLRs (TLR-2, TLR-4, and TLR-5) have been implicated in
mice and humans as signaling receptors for L. monocytogenes
(23, 80, 94, 98). Studies in mice showed that TLR-2 plays a
critical role in controlling Listeria infection (94). In particular,
TLR-2-deficient mice were more susceptible to systemic infec-
tion by Listeria than were wild-type mice, with a reduced sur-
vival rate and an increased bacterial burden in the liver.
HSV. HSV is a formidable pathogen causing disseminated or
central nervous system disease with a high mortality rate in the
first weeks of life (101). Infection is acquired during the birth
process as the neonate comes in contact with the virus during
passage through an infected birth canal or through contact
with individuals with active HSV lesions. Cellular immune
responses mediated by T cells are impaired in newborns com-
MINIREVIEW 2001
pared with older children and adults, which may be responsible
for rapid progression of the disease (14, 86). Recent studies
have shown that both HSV-1 and HSV-2 induced secretion of
IL-6 and IL-8 from adult peripheral blood mononuclear cells
(PBMCs) in a dose-dependent manner (41). In addition,
HSV-1 and HSV-2 activated NF-␬B in TLR-2-transfected
HEK 293 cells but not control HEK cells or TLR-4-transfected
HEK cells (40). Analysis of IL-6 and IL-8 responses revealed
that cord blood cells produced significantly higher amounts of
these cytokines in response to stimulation with HSV-1 than did
adult blood cells (40). These findings are in concert with pre-
viously published data indicating that term and preterm infants
produce enhanced IL-6 and IL-8 and that clinical manifesta-
tion of HSV infection is associated with increased production
of inflammatory cytokines (79). Nevertheless, the link between
in vitro and in vivo data is only indirect, and further research is
needed to determine whether ongoing overproduction of in-
flammatory cytokines is a consistent component of HSV pa-
thology in newborns.
The effect of FL on neonatal innate immunity to HSV
infection has recently been studied in mice (95). After FL
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treatment, the nature and quality of resistance were ana-
lyzed for short-term innate effect and for survival of neona-
tal mice. Data showed that FL induced an IFN-␣/␤-associ-
ated immune response in newborn animals by expanding
cells of the DC linage. A significant number of mice lacking
mature T and B cells died after challenge with HSV-1,
whereas 30 to 40% of FL-treated mice survived HSV-1
infection for more than 21 days (95). This observation indi-
cated that innate immunity was decisive in defense against
HSV and that manipulation of the innate immune system by
cytokine treatment may provide a tool to improve clinical
outcomes of neonatal HSV infection.
CMV. CMV is the most common cause of intrauterine in-
fection, affecting 0.3 to 2.2% of live-born infants (4). Congen-
ital CMV infection is a leading cause of sensorineural hearing
loss, cognitive and visual impairment, and cerebral palsy. The
virus can be transmitted to the fetus during primary maternal
infection in pregnancy, but it can also be transmitted even
when maternal infection occurred years prior to conception
(24, 81). Earlier studies suggested that the increased suscepti-
bility of the fetus to CMV infection could be related to defec-
tive cell-mediated immunity (26, 67). Recently, the presence of
functionally mature cytolytic CD8⫹ T lymphocytes in newborns
with congenital CMV infection was reported (47). This finding
suggests that intrauterine antigen stimulation has the potential
to elicit protective immunity in the fetus and that, in contrast
to CD4⫹ T cells, the expression of efficient CD8⫹ effector
function in newborns may be preserved. Pertinent to this find-
ing, functionally mature CD8⫹ cytotoxic responses were doc-
umented in infants during primary infection with RSV (61).
The overall efficiency of CD8-dependent T-cell function in
fetal or neonatal life, however, remains unclear. Evidence sug-
gests that neonatal CD4⫹ T cells are deficient in activation-
associated intracellular signaling and require high levels of
costimulation to achieve maximal activation (2, 27, 96). In this
regard it is noteworthy that CD4⫹ T cells play an essential
role in promoting the long-term activation and terminal
differentiation of CD8⫹ T cells and in reactivation of CD8⫹
memory cells.
2002 MINIREVIEW
CMV, as a cofactor, may be involved in the pathogenesis of
HIV infection and AIDS (72). A cohort-based prospective
study was performed to examine the possible association of
CMV infection with the progression of HIV disease in infants
who were born to HIV-1-infected women and whose CMV
status was known (38). At birth, the frequency of CMV infec-
tion in HIV-1-infected infants and in infants not infected with
HIV-1 was 4.3% and 4.5%, respectively, which was higher than
the rates of 0.3 to 2.2% in the general population. However, at
6 months of age, CMV infection was diagnosed in 39.9% of
HIV-1-infected infants and in only 15.3% of noninfected in-
fants. The cumulative rates of CMV infection over a period of
48 months remained significantly higher among HIV-1-in-
fected children, and the rate of CMV transmission from moth-
ers to offspring was especially high during the first 12 months
(38). These data suggest that HIV-1-infected children have a
higher rate of CMV infection acquired postnatally and that
CMV infection is associated with an increased risk of HIV-1
disease progression. It is likely that CMV and HIV-1, two
immunosuppressive viruses, may act synergistically to acceler-
ate disease progression. Whatever the mechanism, these ob-
servations suggest that strategies to prevent vertical and hori-
zontal CMV infection in HIV-1-infected infants and children
should be applied in order to decrease and prolong disease
progression and central nervous system disease.
EBV. EBV infection occurring in early childhood is usually
not associated with any defined clinical disease (87). However,
if primary infection is delayed until adolescence or adulthood,
a high proportion of affected individuals develop infectious
mononucleosis (IM), characterized by increased numbers of
EBV-infected B cells in the peripheral blood and massive
oligoclonal expansion of EBV-specific CD8⫹ T cells (88). IM
can be expected to occur when primary EBV infection is not
adequately controlled, leading to a subsequent overstimulation
of CD8⫹ T cells by EBV-infected B cells. This concept is in
agreement with fulminant IM occurring in patients with X-
linked lymphoproliferative disease, an inherited immune defi-
ciency characterized by defective immune responses to EBV
infection. However, this would also imply that EBV infection
may be controlled better in newborns and infants than in ad-
olescents or adults. Recently, there have been a number of
studies of CD4⫹ T cells, which are able to inhibit EBV-trans-
formed lymphoblastoid B cell line growth (89, 103). These
transformed B cells can activate CD4⫹ T cells and NK cells
from both adult and fetal blood. Differences in the activities of
CD4⫹ T cells and NK cells may not explain the immunological
and clinical phenotypes of EBV infection in different age
groups. However, CD8⫹ T-cell responses to EBV-infected B
cells may be weaker in newborns and infants, explaining the
lack of clinical manifestation of infection in early life.
VZV. VZV may cause significant morbidity and mortality in
fetuses and newborns, and vaccinating VZV-susceptible
women prior to pregnancy can prevent both vertical and hor-
izontal transmission of varicella, suggesting a role for antibody-
mediated immunity (68). Fetal varicella syndrome arises in
about 2% of cases of maternal varicella, occurring during the
first 20 weeks of gestation (68, 70). VZV infection in newborns
may result from either vertical or horizontal transmission. Peri-
natally acquired varicella occurs mostly after the onset of ma-
ternal viremia but before maternal antibody develops. Visceral
INFECT. IMMUN.
organ involvement and a high mortality rate are characteristic
features of perinatal varicella (13). Innate immunity in the
“antibody-free” window period is therefore critical to control
infection. PBMCs from adults were found to produce a large
amount of IFN-␥ in response to VZV antigen, suggesting that
a Th1 response with IFN-␥ production may be important in
early host defense against VZV (7, 30). Remarkably, VZV did
not drive cord blood mononuclear cells (MC) to release sig-
nificant IFN-␥ production (107). A real-time reverse-transcrip-
tion PCR analysis of IFN-␥ mRNA expression showed that
VZV induced a significantly higher IFN-␥ mRNA in PBMCs
than in cord blood MC. IFN-␥ production is regulated by T-bet
expression mediated by STAT-1 (signal transducer and activa-
tor of transcription 1) (3, 73). Recent data suggested that VZV
did not upregulate T-bet mRNA significantly in cord blood
MC in contrast to its effect in adult PBMCs. These data indi-
cate a poor Th1 response and an impaired innate immune
response to VZV in neonates.
RSV. RSV infection is one of the most common human viral
diseases worldwide, and virtually every child is infected by the
third birthday (66). The virus does not normally replicate out-
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side of the bronchopulmonary tree, and the infection is exquis-
itely restricted to the respiratory mucosa. RSV proteins such as
the major surface glycoprotein (G) and the fusion (F) protein,
which is a large envelope glycoprotein, are essential for viral
attachment and penetration, respectively, and are important in
initiating immune responses (66, 99). Both G and F glycopro-
teins are able to induce neutralizing antibody responses and
long-term immunity. However, in young infants antibody-me-
diated immunity might contribute to lung pathology as well.
Despite the presence through the first few months of life of
maternal antiviral antibodies passively transferred to the fetus,
prevalence of more severe forms of RSV disease is greatest in
young infants. In a cohort of infants, not only did maternal
neutralizing antibodies fail to prevent infection with RSV, but
also the severity of pneumonia was inversely related to the
level of neutralizing antibodies, an intriguing observation as far
as passive neonatal immunity is concerned (39, 42). In contrast,
administration of RSV-specific immunoglobulin or monoclo-
nal antibody preparations to high-risk infants may prevent
bronchiolitis and hospitalization (33, 71). These data clearly
indicate that further research is needed to define the role of
specific antibodies in antiviral immunity in RSV disease in
early life.
Several reports suggested detectable innate cytokine re-
sponses to RSV at birth. In vitro, both cord and adult mono-
cyte-derived macrophages exhibited production of high levels
of IL-6 and TNF-␣ within 24 h after viral exposure (60). In
contrast to adult cells, little or no production by cord macro-
phages of these cytokines was observed 24 h after exposure to
live RSV. These data indicated that neonatal macrophages
may be less efficient in a sustained induction of inflammatory
cytokine production. Others found that cord mononuclear cells
showed no proliferation response to exposure to inactivated
RSV and, when exposed to live virus, produced fewer innate
and no adaptive cytokines (39). The major difference in cyto-
kine responses of cord and adult mononuclear cells to RSV
exposure appears to be that cord cells produce almost entirely
innate cytokines, whereas both innate and adaptive cytokines
are produced by adult cells. Consequently, adaptive cytokine
VOL. 74, 2006
responses may be required for an efficient innate immune
response to RSV. Humans are born with the capacity to mount
innate cytokine responses to RSV, but due to the lack of in
utero sensitization, infants may remain highly susceptible to
the virus until adaptive cellular immunity develops.
In mice sensitized with recombinant vaccinia virus vector, the G
and F glycoproteins differentially regulated cytokine responses
(5). Whereas G protein induced a Th2-type response character-
ized by secretion of IL-4 and IL-5, F protein induced the secretion
of IL-2 and IFN-␥. In addition to inflammatory and immunoregu-
latory cytokines, chemokines are also induced in the respiratory
tract after natural RSV infection. Studies of children with RSV
bronchiolitis have shown an increased production of chemokines
including CXCL8, CXCL5, CXCL3, and CXCL2 in the upper
respiratory tract (32, 65). Intriguing recent findings on chemokine
production in the lower respiratory tract in infants with RSV
bronchiolitis were reported (63). CXC chemokines (CXCL10 and
CXCL8) were found to be the most abundant, but CC chemo-
kines (CCL2 and CCL3) were also present. Remarkably,
CXCL10, one of the few chemokines capable of binding receptors
from different classes (both CXCR3 and CCR3), was present in
very large quantity in the RSV-infected lung. Whether chemokine
responses are protective or contribute to the pathogenesis of RSV
disease needs to be determined. Further clinical studies are re-
quired to discover whether chemokine responses induced by RSV
occur in other viral or respiratory tract infections in children.
Precise elucidation of the role of chemokines in the pathogenesis
of RSV bronchiolitis has potentially therapeutic implications be-
cause a number of chemokine receptor antagonists are in devel-
opment.
The clinical spectrum of RSV disease is extremely variable,
ranging from mild upper-respiratory tract disease to severe
respiratory distress (66). It is likely that genetic heterogeneity
contributes to disease severity in addition to known risk factors
including prematurity, congenital heart anomaly, and chronic
lung disease. Efficient host immune responses to viral patho-
gens are mediated by Th1 cytokines. As the production of Th1
cytokines can be inhibited by cytokines secreted by Th2 lym-
phocytes, an adequate balance of Th1 and Th2 cytokines is
essential for the efficient eradication of RSV. Several studies
have shown a correlation between predominant Th2 responses
in infants with RSV disease severity (1, 12, 74). TLR-4 and
CD14 have been shown to sense RSV, and TLR-4-deficient
mice developed delayed clearance of RSV as well as a pre-
dominant Th2 response which correlated with disease progres-
sion (29, 92). An association between TLR-4 mutations
(Asp299Gly and Thr394Ile) and severe RSV disease has re-
cently been reported, whereas no association between CD14
polymorphisms and RSV bronchiolitis was found (92).
Toxoplasma. T. gondii, an obligate intracellular pathogen,
causes subclinical chronic infections in humans, where it is also
an important opportunistic pathogen (62). The human fetus
and newborn are especially susceptible to infection by T. gon-
dii. The placenta may act as a barrier to transplacental trans-
mission of parasites from mother to fetus, which occurs mostly
in the third trimester. In congenitally infected newborns, in-
fections with T. gondii may result in fibrous or calcified cerebral
lesions or ocular lesions that threaten vision (62). However,
disseminated infection is rare in congenitally infected infants
(20). This may be explained by the unique process of gliding
MINIREVIEW 2003
motility that is used by T. gondii organisms to actively invade
their vertebral host cells (100). Calcium-mediated protein se-
cretion and MIC2, a thrombospondin-related protein that
serves as adhesion for T. gondii, have been implicated in the
process of gliding motility. By using this invasion strategy,
Toxoplasma escapes phagocytic uptake, and the host cell plays
little role in controlling the entry of the parasite. During pen-
etration of host cells, T. gondii restricts access of host cell
proteins to the vacuole, thus creating a fusion-incompetent
vacuole that lies segregated from the endocytic network (100).
This unique intracellular lifestyle provides protection from
host surveillance.
Defense against T. gondii infection is mediated primarily by
cellular responses involving killing by macrophages and cyto-
toxic T cells and release of inflammatory cytokines that help
infected cells to kill the parasite or to maintain it in a quiescent
stage. Cellular immunity is mainly targeted to infected cells
that express peptides from the parasite (21). Killing of Toxo-
plasma by and the survival and replication of this parasite in
resident mononuclear phagocytes from newborns and adults,
respectively, are comparable (104, 105). In the immune mech-
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anism through which acute T. gondii infection is controlled,
IFN-␥ plays a central role as a strong activator of resident
macrophages to limit intracellular growth of tachyzoites. In
vitro studies showed that GTPases are required for IFN-␥-
induced suppression of T. gondii growth in macrophages (15).
In particular, a 47-kDa protein that possesses inherent GTPase
activity and binds to the endoplasmic reticulum and Golgi was
found to regulate host resistance to T. gondii through its ability
to inhibit parasite growth within the macrophage. In human
newborns, both generation of IFN-␥ and response to IFN-␥ by
mononuclear phagocytes are impaired (49, 104). This age-
related deficiency is likely to be one critical factor responsible
for the increased susceptibility of newborns to T. gondii infec-
tion.
Candida. Infections by Candida are the most common of the
fungal infections in newborns (8, 83). Body surfaces are colo-
nized at birth by Candida species residing in the birth canal.
Overgrowth of colonizing Candida may lead to mucosal or
mucocutaneous candidiasis. The role of passively acquired hu-
moral antibody in defense against invasive candidal disease
appears to be negligible in newborns (48). The unique suscep-
tibility to oropharyngeal candidiasis during the first weeks re-
sults most likely from the down-regulation of Th1 responses
(43, 48, 49).
Invasive candidal disease in neonates is a life-threatening
condition which may be explained by developmental deficien-
cies in the newborn’s innate immune system (52). Candida
albicans is part of the common commensal of the gastrointes-
tinal tract and invasive candidal disease can arise from entero-
circular translocation of the gut flora (58, 77). B cell knockout
mice, which lack functional antibodies, are as resistant to mu-
cosal or invasive candidiasis of endogen origin as are immuno-
competent controls (97). In addition, patients with X-linked
agammaglobulinemia or severe hypogammaglobulinemia do
not exhibit an increased susceptibility to either mucocutaneous
or invasive candidal infections (52). In such patients T cells and
innate immune cells ensure defense against Candida, and macro-
phages can prevent candidal invasion by phagocytosis and kill-
2004 MINIREVIEW
ing of nonopsonized yeasts through innate immune receptors
(19, 25, 54, 90).
Recognition and uptake of Candida yeasts involve the macro-
phage MR, which is a type I membrane protein with three types
of domains in the extracellular region (19, 54, 59, 93). Well-
characterized lectin activities of the MR are mediated by the
cysteine-rich domain which can recognize sulfated sugars,
whereas mannose recognition takes place through the C-type
lectin-like domains. The extent of phagocytosis and killing of
nonopsonized Candida organisms by resident monocyte-derived
macrophages were comparable in newborns and adults, and both
mannan and mannose-bovin serum albumin complex inhibited
ingestion in a concentration-dependent manner, suggesting a role
for the MR (50, 52). Exposure of adult macrophages to IFN-␥ (up
to a concentration 100 U/ml) resulted in increased phagocytosis
and killing. In contrast, no enhancement with cord macrophages
could be detected under the same experimental condition, and at
a concentration of 500 U/ml IFN-␥ there was still significantly
lower killing and superoxide release by cord macrophages com-
pared to adult cells (57). These data suggested that neonatal
macrophages have a normal capacity to ingest and kill Candida
through the MR but cannot be fully activated by IFN-␥, a finding
that could not be attributed to lower expression or binding to its
ligand of IFN-␥ receptor on neonatal cells. Remarkably, in re-
sponse to IFN-␥, a significantly decreased STAT-1 phosphoryla-
tion was detected in neonatal cells, suggesting the possibility of
negative regulation of IFN-␥ receptor signaling in newborns (51).
The precise mechanism by which signaling through innate im-
mune receptors may be down-modulated in neonates remains
unclear.
Dectin-1, the receptor for binding fungal-derived ␤-glucan
by macrophages and neutrophils, is a small type II transmem-
brane protein containing one lectin-like carbohydrate recogni-
tion domain (25). This receptor can recognize live Saccharo-
myces cerevisiae and, to a lesser extent, C. albicans. It was
previously reported that ligand binding to the MR is not cou-
pled to the activation of the respiratory burst oxydase and
superoxide release in macrophages, in contrast to binding an-
tibody-opsonized Candida to Fc receptors on these cells (54).
The effect of ligand binding to dectin-1 on the respiratory burst
activity has not been studied. However, a TNF-␣ response was
generated by macrophages upon exposure to ␤-glucan. Re-
markably, the production of TNF-␣ was significantly greater
when macrophages were exposed to S. cerevisiae than to C.
albicans. This observation is in concert with published data that
␤-glucan is buried within the cell wall of C. albicans and that
Candida uptake by macrophages and keratinocytes can be in-
hibited by mannan and, to a lower extent, by glucan (37, 54,
90). It is also possible that S. cerevisiae may have a higher
density of ␤-glucan exposed on its surface compared to that of
C. albicans.
SUMMARY AND CONCLUSION
Human neonates are highly susceptible to infection by a
wide range of bacteria, viruses, protozoa, and fungi. The
heightened susceptibility and the severe course of infections in
early life can be attributed, at least in part, to the lack of
preexisting immunological memory and competent adaptive
immunity. In addition, a large body of evidence suggests that
INFECT. IMMUN.
several innate immune mechanisms are impaired in neonates.
It is also clear, however, that neonates are immunocompetent
to mount mature innate as well as adaptive immune responses
like nonopsonic uptake of fungi or, under certain circum-
stances, adult-level T-cell responses. Thus, the challenge of
future research will include the discovery of mechanisms that
underlie differential immune responses in newborns so that
prevention and treatment of neonatal infections can more
safely be targeted.
ACKNOWLEDGMENTS
This work was supported by grants from the Hungarian Research
Fund (OTKA T038095 and OTKA T049017).
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