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19992006
0019-9567/06/$08.000 doi:10.1128/IAI.74.4.19992006.2006
Copyright 2006, American Society for Microbiology. All Rights Reserved.
MINIREVIEW
Neonatal Innate Immunity to Infectious Agents
Laszlo
Maro
di*
Department of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
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).
Host defenses to microbial invasion include the phylogenetically older but rapidly developing antigen-independent or innate 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 nonself, and involve nonspecific activation of neutrophils, monocytes and macrophages, dendritic cells (DCs), natural killer
(NK) cells, and complement. The importance of innate immunity in defense against mycobacteria is illustrated by the observation that patients with T-cell-negative, B-cell-negative,
and NK cell-positive severe combined immunodeficiency
(SCID) may survive inadvertent vaccination with bacillus
Calmette-Guerin vaccine (64).
Phagocytosis as a mechanism of innate immune defense has
served as the classical model for studying host-parasite interactions, and significant progress has been made toward understanding the molecular mechanisms of phagocytic uptake and
microbial killing (19, 25, 54, 57, 59). Recently, Toll-like receptors (TLRs) have emerged as central points of innate immunity
(82, 91). TLRs represent a conserved family of immune receptor 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 immunity is the complement system, which can be activated
through the alternative and lectin pathways, in addition to the
classical pathway, leading to antibody-independent opsonization and opsonophagocytosis (55, 75).
Innate immunity is ontogenetically older than adaptive immunity, 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
2000
MINIREVIEW
ten low and might not have been sufficient for protection.
Naturally occurring IgG antibodies with the capacity to opsonize 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 circulating 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 increased 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. Earlier 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 macrophages 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 phagocytosis, these cells may become permissive for bacterial replication. 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 recently been proposed to be linked to IFN- deficiency in newborns. GBS-stimulated mRNA accumulation and protein secretion of both IFN- and IL-12 in mononuclear cells from
cord and adult blood were studied (36). By using reverse transcriptase PCR and quantitative densitometry assays, the kinetics 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 accumulation 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- deficiency 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.
(45). Perinatal infections caused principally by L. monocytogenes are usually secondary to maternal infection or colonization. Macrophage activation is critically important for an efficient 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). Therefore, even though the innate immunity is effective to provide
protection, an adequate immune response, i.e., clearance of
bacteria, granuloma formation with lymphocytes, and disappearance of microabscesses, requires specific immunity. Adoptive 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 stimulate 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 produced large amounts of cytokines and nitric oxide when exposed to Listeria in vitro. In concert with these findings, newborns treated with CpG ODN were protected from lethal
Listeria challenge (34). These data suggest that cellular elements of the neonatal immune system, similar to those of adult
mice, may respond to stimulation by CpG ODN, thereby reducing 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 increases 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 hematopoietic 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 infection by Listeria than were wild-type mice, with a reduced survival 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-
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