Minireview: Neonatal Innate Immunity To Infectious Agents
Minireview: Neonatal Innate Immunity To Infectious Agents
Minireview: Neonatal Innate Immunity To Infectious Agents
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- responses for innate immune recognition are encoded in the
cally older but rapidly developing antigen-independent or in- germ line DNA and, in contrast to adaptive immune responses,
nate immunity and the much more slowly developing specific do not require gene rearrangement (35).
or adaptive immunity (2, 35, 82, 91). Innate immune responses
are triggered by bacteria, viruses, protozoa, and fungi, as non-
NEONATAL INNATE IMMUNITY
self, and involve nonspecific activation of neutrophils, mono-
cytes and macrophages, dendritic cells (DCs), natural killer Human neonates and young infants are more vulnerable
(NK) cells, and complement. The importance of innate immu- to infectious agents than older children and adults and are
nity in defense against mycobacteria is illustrated by the ob- especially susceptible to infections with intracellular patho-
1999
2000 MINIREVIEW INFECT. IMMUN.
ten low and might not have been sufficient for protection. The capsule of GBS is well characterized as one of the
Naturally occurring IgG antibodies with the capacity to opson- virulence factors of streptococci. The capsule protects GBS
ize GBS type III in a complement-dependent manner may also from opsonization by C3 through inhibition of the alternative
play a role in host defense against these pathogens (22). complement pathway in the absence of type-specific antibodies
Neutrophils are the predominant mobile phagocytes of cir- (76). In addition, streptococcal proteins localized to the sur-
culating blood and may contribute to killing of GBS even more face of bacteria may bind complement factor H, retaining its
than mononuclear phagocytes do. Importantly, exposure to ability to down-regulate complement activation (6). Recently,
recombinant human IFN-␥ was found to activate cord blood a surface-localized protease, CspA, that may play an important
neutrophils and to result in enhanced chemotaxis and in- role in GBS pathogenesis as an antiphagocytic surface factor
creased concentrations of free intracellular calcium (31). was described (28). CspA was found to be required for GBS
These data suggest that IFN-␥ may enhance the newborns’ cleavage of human fibrinogen. GBS mutants that failed to
own host defense by activating neutrophils. express cspA, the gene coding for CspA, displayed a signifi-
Monocytes and macrophages have a rich diversity of cell cantly decreased virulence in a neonatal rat model of GBS
surface receptors complementing the diversity of microbial infection and an increased sensitivity to opsonophagocytic kill-
molecules that they are likely to encounter, often in the context ing. Further characterization of the expression and function of
of soluble opsonins such as complement and antibodies. Ear- surface-localized GBS proteins and enzymes will help us to
lier studies showed that the capacity of cord blood monocytes understand better how GBS that evade the host innate im-
to kill serum-opsonized GBS type III was decreased compared mune response cause severe infections in newborns.
to the capacity of adult blood monocytes (56). Interactions E. coli. E. coli is one of the leading gram-negative bacteria
between serum-opsonized GBS and monocyte-derived macro- that cause neonatal meningitis and sepsis (84). The mortality
phages isolated from cord blood were also studied by using rate and the neurological squeal remain high despite advances
(45). Perinatal infections caused principally by L. monocyto- pared with older children and adults, which may be responsible
genes are usually secondary to maternal infection or coloniza- for rapid progression of the disease (14, 86). Recent studies
tion. Macrophage activation is critically important for an effi- have shown that both HSV-1 and HSV-2 induced secretion of
cient killing of Listeria, and macrophage activation in vivo by IL-6 and IL-8 from adult peripheral blood mononuclear cells
IFN-␥ is a sine qua non for protection (9, 46). The effectiveness (PBMCs) in a dose-dependent manner (41). In addition,
of innate immunity in host defense against Listeria has been HSV-1 and HSV-2 activated NF-B in TLR-2-transfected
exemplified by studies using SCID mice that lack both T-cell HEK 293 cells but not control HEK cells or TLR-4-transfected
and B-cell immunity. These mice were remarkably resistant to HEK cells (40). Analysis of IL-6 and IL-8 responses revealed
infection with L. monocytogenes due to a rapid neutrophil that cord blood cells produced significantly higher amounts of
response followed by activation of macrophages and were able these cytokines in response to stimulation with HSV-1 than did
to control infection for several days (18). However, listeriosis adult blood cells (40). These findings are in concert with pre-
in mice with an SCID mutation results in a chronic infection viously published data indicating that term and preterm infants
characterized by abundant granulomas, microabscesses, and produce enhanced IL-6 and IL-8 and that clinical manifesta-
neutrophil infiltrates occurring mostly in the liver (11). There- tion of HSV infection is associated with increased production
fore, even though the innate immunity is effective to provide of inflammatory cytokines (79). Nevertheless, the link between
protection, an adequate immune response, i.e., clearance of in vitro and in vivo data is only indirect, and further research is
bacteria, granuloma formation with lymphocytes, and disap- needed to determine whether ongoing overproduction of in-
pearance of microabscesses, requires specific immunity. Adop- flammatory cytokines is a consistent component of HSV pa-
tive transfer studies showed a decisive role of CD4⫹ and CD8⫹ thology in newborns.
T cells in augmenting innate antibacterial host defenses and The effect of FL on neonatal innate immunity to HSV
ensuring long-term survival of Listeria-infected adult mice (11). infection has recently been studied in mice (95). After FL
CMV, as a cofactor, may be involved in the pathogenesis of organ involvement and a high mortality rate are characteristic
HIV infection and AIDS (72). A cohort-based prospective features of perinatal varicella (13). Innate immunity in the
study was performed to examine the possible association of “antibody-free” window period is therefore critical to control
CMV infection with the progression of HIV disease in infants infection. PBMCs from adults were found to produce a large
who were born to HIV-1-infected women and whose CMV amount of IFN-␥ in response to VZV antigen, suggesting that
status was known (38). At birth, the frequency of CMV infec- a Th1 response with IFN-␥ production may be important in
tion in HIV-1-infected infants and in infants not infected with early host defense against VZV (7, 30). Remarkably, VZV did
HIV-1 was 4.3% and 4.5%, respectively, which was higher than not drive cord blood mononuclear cells (MC) to release sig-
the rates of 0.3 to 2.2% in the general population. However, at nificant IFN-␥ production (107). A real-time reverse-transcrip-
6 months of age, CMV infection was diagnosed in 39.9% of tion PCR analysis of IFN-␥ mRNA expression showed that
HIV-1-infected infants and in only 15.3% of noninfected in- VZV induced a significantly higher IFN-␥ mRNA in PBMCs
fants. The cumulative rates of CMV infection over a period of than in cord blood MC. IFN-␥ production is regulated by T-bet
48 months remained significantly higher among HIV-1-in- expression mediated by STAT-1 (signal transducer and activa-
fected children, and the rate of CMV transmission from moth- tor of transcription 1) (3, 73). Recent data suggested that VZV
ers to offspring was especially high during the first 12 months did not upregulate T-bet mRNA significantly in cord blood
(38). These data suggest that HIV-1-infected children have a MC in contrast to its effect in adult PBMCs. These data indi-
higher rate of CMV infection acquired postnatally and that cate a poor Th1 response and an impaired innate immune
CMV infection is associated with an increased risk of HIV-1 response to VZV in neonates.
disease progression. It is likely that CMV and HIV-1, two RSV. RSV infection is one of the most common human viral
immunosuppressive viruses, may act synergistically to acceler- diseases worldwide, and virtually every child is infected by the
ate disease progression. Whatever the mechanism, these ob- third birthday (66). The virus does not normally replicate out-
responses may be required for an efficient innate immune motility that is used by T. gondii organisms to actively invade
response to RSV. Humans are born with the capacity to mount their vertebral host cells (100). Calcium-mediated protein se-
innate cytokine responses to RSV, but due to the lack of in cretion and MIC2, a thrombospondin-related protein that
utero sensitization, infants may remain highly susceptible to serves as adhesion for T. gondii, have been implicated in the
the virus until adaptive cellular immunity develops. process of gliding motility. By using this invasion strategy,
In mice sensitized with recombinant vaccinia virus vector, the G Toxoplasma escapes phagocytic uptake, and the host cell plays
and F glycoproteins differentially regulated cytokine responses little role in controlling the entry of the parasite. During pen-
(5). Whereas G protein induced a Th2-type response character- etration of host cells, T. gondii restricts access of host cell
ized by secretion of IL-4 and IL-5, F protein induced the secretion proteins to the vacuole, thus creating a fusion-incompetent
of IL-2 and IFN-␥. In addition to inflammatory and immunoregu- vacuole that lies segregated from the endocytic network (100).
latory cytokines, chemokines are also induced in the respiratory This unique intracellular lifestyle provides protection from
tract after natural RSV infection. Studies of children with RSV host surveillance.
bronchiolitis have shown an increased production of chemokines Defense against T. gondii infection is mediated primarily by
including CXCL8, CXCL5, CXCL3, and CXCL2 in the upper cellular responses involving killing by macrophages and cyto-
respiratory tract (32, 65). Intriguing recent findings on chemokine toxic T cells and release of inflammatory cytokines that help
production in the lower respiratory tract in infants with RSV infected cells to kill the parasite or to maintain it in a quiescent
bronchiolitis were reported (63). CXC chemokines (CXCL10 and stage. Cellular immunity is mainly targeted to infected cells
CXCL8) were found to be the most abundant, but CC chemo- that express peptides from the parasite (21). Killing of Toxo-
kines (CCL2 and CCL3) were also present. Remarkably, plasma by and the survival and replication of this parasite in
CXCL10, one of the few chemokines capable of binding receptors resident mononuclear phagocytes from newborns and adults,
from different classes (both CXCR3 and CCR3), was present in respectively, are comparable (104, 105). In the immune mech-
ing of nonopsonized yeasts through innate immune receptors several innate immune mechanisms are impaired in neonates.
(19, 25, 54, 90). It is also clear, however, that neonates are immunocompetent
Recognition and uptake of Candida yeasts involve the macro- to mount mature innate as well as adaptive immune responses
phage MR, which is a type I membrane protein with three types like nonopsonic uptake of fungi or, under certain circum-
of domains in the extracellular region (19, 54, 59, 93). Well- stances, adult-level T-cell responses. Thus, the challenge of
characterized lectin activities of the MR are mediated by the future research will include the discovery of mechanisms that
cysteine-rich domain which can recognize sulfated sugars, underlie differential immune responses in newborns so that
whereas mannose recognition takes place through the C-type prevention and treatment of neonatal infections can more
lectin-like domains. The extent of phagocytosis and killing of safely be targeted.
nonopsonized Candida organisms by resident monocyte-derived
macrophages were comparable in newborns and adults, and both ACKNOWLEDGMENTS
mannan and mannose-bovin serum albumin complex inhibited This work was supported by grants from the Hungarian Research
ingestion in a concentration-dependent manner, suggesting a role Fund (OTKA T038095 and OTKA T049017).
for the MR (50, 52). Exposure of adult macrophages to IFN-␥ (up
REFERENCES
to a concentration 100 U/ml) resulted in increased phagocytosis
1. Aberle, J. H., S. W. Aberle, M. N. Dworzak, C. W. Mandl, W. Rebhandl, G.
and killing. In contrast, no enhancement with cord macrophages Vollnhofer, M. Kundi, and T. Popow-Kraupp. 1999. Reduced interferon-
could be detected under the same experimental condition, and at gamma expression in peripheral blood mononuclear cells of infants with
a concentration of 500 U/ml IFN-␥ there was still significantly severe respiratory syncytial virus disease. Am. J. Respir. Crit. Care Med.
160:1263–1268.
lower killing and superoxide release by cord macrophages com- 2. Adkins, B., C. Leclerc, and S. Marshall-Clarke. 2004. Neonatal adaptive
pared to adult cells (57). These data suggested that neonatal immunity comes of age. Nat. Rev. Immunol. 4:553–564.
macrophages have a normal capacity to ingest and kill Candida 3. Afkarian, M., J. R. Sedy, J. Yang, N. G. Jacobson, N. Cereb, S. Y. Yang,
congenitally infected newborns and immunocompetent infected hosts. Eur. 45. Lorber, B. 1997. Listeriosis. Clin. Infect. Dis. 24:1–9.
J. Clin. Microbiol. Infect. Dis. 22:181–184. 46. Mackaness, G. B. 1962. Cellular resistance to infection. J. Exp. Med. 116:
21. Fatoohi, A. F., G. J. Cozon, P. Gonzalo, M. Mayencon, T. Greenland, S. 381–406.
Picot, and F. Peyron. 2004. Heterogeneity in cellular and humoral immune 47. Marchant, A., V. Appay, M. Van Der Sande, N. Dulphy, C. Liesnard, M. Kidd,
responses against Toxoplasma gondii antigen in humans. Clin. Exp. Immu- S. Kaye, O. Ojuola, G. M. Gillespie, A. L. Vargas Cuero, V. Cerundolo, M.
nol. 136:535–541. Callan, K. P. McAdam, S. L. Rowland-Jones, C. Donner, A. J. McMichael, and
22. Feldman, R. G., M. A. Breukels, S. David, and G. T. Rijkers. 1998. Prop- H. Whittle. 2003. Mature CD8(⫹) T lymphocyte response to viral infection
erties of human anti-group B streptococcal type III capsular IgG antibody. during fetal life. J. Clin. Investig. 111:1747–1755.
Clin. Immunol. Immunopathol. 86:161–169. 48. Maródi, L. 1997. Local and systemic host defense mechanisms against
23. Flo, T. H., O. Halaas, E. Lien, L. Ryan, G. Teti, D. T. Golenbock, A. Sundan, Candida: immunopathology of candidal infections. Pediatr. Infect. Dis. J.
and Espevik, T. 2000. Human Toll-like receptor 2 mediates monocyte 16:795–801.
activation by Listeria monocytogenes, but not by group B streptococci or 49. Maródi, L. 2002. Down-regulation of Th1 responses in human neonates.
lipopolysaccharide. J. Immunol. 164:2064–2069. Clin. Exp. Immunol. 128:1–2.
24. Fowler, K. B., S. Stagno, and R. F. Pass. 2003. Maternal immunity and 50. Maródi, L., D. E. Campbell, R. Káposzta, R. A. Polin, J. Csongor, and R. B.
prevention of congenital cytomegalovirus infection. JAMA 289:1008–1011. Johnston, Jr. 1994. Candidacidal mechanisms in the human neonate: im-
25. Gantner, B. N., R. M. Simmons, and D. M. Underhill. 2005. Dectin-1 paired IFN-gamma activation of macrophages in newborn infants. J. Im-
mediates macrophage recognition of Candida albicans yeast but not fila- munol. 153:5643–6549.
ments. EMBO J. 24:1277–1286. 51. Maródi, L., K. Goda, A. Palicz, and G. Szabó. 2001. Cytokine receptor
26. Gehrz, R. C., S. C. Marker, S. O. Knorr, J. M. Kalis, and H. H. Balfour. signaling in neonatal macrophages: defective STAT-1 phosphorylation in
1977. Specific cell-mediated immune defect in active cytomegalovirus in- response to stimulation with IFN-␥. Clin. Exp. Immunol. 126:456–460.
fection of young children and their mothers. Lancet 2:844–847. 52. Maródi, L., and R. B. Johnston, Jr. 2003. Mechanisms of resistance to
27. Han, P., T. McDonald, and G. Hodge. 2004. Potential immaturity of the fungal infections, p. 1487–1489. In R. A. Polin, W. W. Fox, and S. Abman
T-cell and antigen-presenting cell interaction in cord blood with particular (ed.), Fetal and neonatal physiology. Elsevier, Philadelphia, Pa.
emphasis on the CD40-CD40 ligand costimulatory pathway. Immunology 53. Maródi, L., R. Káposzta, and É. Nemes. 2000. Survival of group B Strep-
113:26–34. tococcus type III in mononuclear phagocytes: differential regulation of
28. Harris, T. O., D. W. Shelver, J. F. Bohnsack, and C. E. Rubens. 2003. A bacterial killing in cord macrophages by human recombinant gamma inter-
novel streptococcal surface protease promotes virulence, resistance to op- feron and granulocyte-macrophage colony-stimulating factor. Infect. Im-
sonophagocytosis, and cleavage of human fibrinogen. J. Clin. Investig. 111: mun. 68:2167–2170.
61–70.
protein mediates serum resistance of Escherichia coli K1. J. Immunol. 89. Sun, Q., R. L. Burton, K. E. Pollok, D. J. Emanuel, and K. G. Lucas. 1999.
169:6352–6360. CD4(⫹) Epstein-Barr virus-specific cytotoxic T-lymphocytes from human
70. Preblud, S. R., D. J. Bregman, and L. L. Vernon. 1985. Deaths from umbilical cord blood. Cell. Immunol. 195:81–88.
varicella in infants. Pediatr. Infect. Dis. J. 4:503–507. 90. Szolnoky, G., Z. Bata-Csörgó, A. S. Kenderessy, M. Kiss, A. Pivarcsi, Z.
71. The Prevent Study Group. 1997. Reduction of respiratory syncytial virus Novák, K. Nagy Newman, G. Michel, T. Ruzicka, L. Maródi, A. Dobozy, and
hospitalization among premature infants and infants with bronchopulmo- L. Kemény. 2001. A mannose-binding receptor is expressed on human
nary dysplasia using respiratory syncytial virus immune globulin prophy- keratinocytes and mediates killing of Candida albicans. J. Investig. Derma-
laxis. Pediatrics 99:93–99. tol. 117:205–213.
72. Rabkin, C. S., A. Hatzakis, P. D. Griffiths, D. Pillay, M. V. Ragni, M. W. 91. Takeda, K., and S. Akira. 2005. Toll-like receptors in innate immunity. Int.
Hilgartner, J. J. Goedert, et al. 1993. Cytomegalovirus infection and risk of Immunol. 17:1–14.
AIDS in human immunodeficiency virus-infected hemophilia patients. 92. Tal, G., A. Mandelberg, I. Dalal, K. Cesar, E. Somekh, A. Tal, A. Oron, S.
J. Infect. Dis. 168:1260–1263. Itskovich, A. Ballin, S. Houri, A. Beigelman, O. Lider, G. Rechavi, and N.
73. Robinson, D. S., and A. O’Garra. 2002. Further checkpoints in Th1 devel- Amariglio. 2004. Association between common Toll-like receptor 4 muta-
tions and severe respiratory syncytial virus disease. J. Infect. Dis. 189:2057–
opment. Immunity 16:755–758.
2063.
74. Roman, M., W. J. Calhoun, K. L. Hinton, L. F. Avendano, V. Simon, A. M.
93. Taylor, M. E., J. T. Conary, M. R. Lennartz, P. D. Stahl, and K. Drickamer.
Escobar, A. Gaggero, and P. V. Diaz. 1997. Respiratory syncytial virus
1990. Primary structure of the mannose receptor contains multiple motifs
infection in infants is associated with predominant Th-2-like response.
resembling carbohydrate-recognition domains. J. Biol. Chem. 265:12156–
Am. J. Respir. Crit. Care Med. 156:190–195.
12162.
75. Rooijakkers, S. H., M. Ruyken, A. Roos, M. R. Daha, J. S. Presanis, R. B. 94. Torres D., M. Barrier, F. Bihl, V. J. Quesniaux, I. Maillet, S. Akira, B.
Sim, W. J. van Wamel, K. P. van Kessel, and J. A. van Strijp. 2005. Immune Ryffel, and F. Erard. 2004. Toll-like receptor 2 is required for optimal
evasion by a staphylococcal complement inhibitor that acts on C3 conver- control of Listeria monocytogenes infection. Infect. Immun. 72:2131–2139.
tases. Nat. Immunol. 6:920–927. 95. Vollstedt, S., M. Franchini, H. P. Hefti, B. Odermatt, M. O’Keeffe, G. Alber,
76. Rubens, C. E., M. R. Wessels, L. M. Heggen, and D. L. Kasper. 1987. B. Glanzmann, M. Riesen, M. Ackermann, and M. Suter. 2003. Flt3 ligand-
Transposon mutagenesis of type III group B Streptococcus: correlation of treated neonatal mice have increased innate immunity against intracellular
capsule expression with virulence. Proc. Natl. Acad. Sci. USA 84:7208– pathogens and efficiently control virus infections. J. Exp. Med. 197:575–584.
7212. 96. Vollstedt, S., M. O’Keeffe, B. Odermatt, R. Beat, B. Glanzmann, M. Riesen,
77. Scherer, S., and D. A. Stevens. 1988. Candida albicans dispersed, repeated K. Shortman, and M. Suter. 2004. Treatment of neonatal mice with Flt3
gene family and its epidemiological applications. Proc. Natl. Acad. Sci. ligand leads to changes in dendritic cell subpopulations associated with
Editor: J. B. Kaper