Review
Placental Plasmodium falciparum infection: Causes and consequences of in utero sensitization to parasite antigens

https://doi.org/10.1016/j.molbiopara.2006.10.001Get rights and content

Abstract

Available evidence suggests that, in African populations, systemic blood-dwelling parasitoses of mothers are associated with enhanced susceptibility to infection of their offspring. Thus, children born to mothers with filariasis or schistosomiasis are infected earlier, and offspring of mothers with placental Plasmodium falciparum at delivery, commonly referred to as pregnancy-associated malaria or PAM, are themselves at higher risk of developing parasitaemia during infancy. Since foetal/neonatal antigen-presenting cells (APC) are either immature or provide insufficient costimulatory signals to T cells, thus favouring tolerance induction, it is commonly assumed that soluble parasite components [protein antigens], transferred transplacentally and inducing foetal immune tolerance, are largely, if not exclusively, responsible for these outcomes. Plasmodial asexual blood stage antigen-specific T cells are detectable in as many as two-thirds of all cord blood samples in malaria-endemic countries of sub-Saharan Africa, indicating that in utero sensitization may be a common phenomenon during pregnancy in these populations. Parasite antigen-specific T cell responses of neonates born to helminth-infected mothers display a highly skewed Th2-type cytokine pattern, with a prominent role for the regulatory cytokine interleukin (IL)-10. Similarly, the cord blood immune response of those born to mothers identified with on-going PAM is characterised by inducible parasite antigen-specific IL-10-producing regulatory T cells that can inhibit both APC HLA expression and Th1-type T cell responses. In contrast, plasmodial antigen-specific Th1-type responses, characterised by IFN-γ production, predominate in cord blood of those born to mothers successfully treated for Pf malaria during gestation, suggesting that the duration and/or the nature of antigen exposure in utero governs the outcome with respect to neonatal immune responses. Aspects of APC function in the context of these differentially modulated responses, whether and how the latter translate into altered susceptibility to Pf infection during infancy, as well as the possible implications for vaccination in early life, are aspects that are discussed in this review.

Section snippets

Foreword

Several aspects of the immunology and pathogenesis of pregnancy-associated Plasmodium falciparum (Pf) malaria (PAM), including maternal antibody- and cell-mediated responses to placental infection, have been reviewed recently and will not be addressed in detail here [1], [2], [3]. This review deals specifically with PAM-associated cellular immunological activity from the maternal but particularly from the foetal perspective. The choice of focus on the latter relates to its relative neglect as a

Neonatal immunity: APC and T cell interactions in the absence of PAM

Neonates have comparatively poor immune responses. One of the explanations could be that neonatal T cells are not yet fully developed, but, since mammals with a gestational period longer than 60 days already have mature immune systems before birth (reviewed in [22]), this is unlikely. Lymphocytes are present in the human foetal circulation between 7 and 8 weeks. T cells develop subsequently in the thymus and by week 12 they express a T cell receptor (TCR). By mid-gestation alloreactive T cells

Materno-foetal transfer across the syncytiotrophoblast & PAM

Reliable reports of the presence of Pf-infected erythrocytes (Pf-iE) in cord blood i.e. those studies where appropriate precautions were taken to exclude the possibility of contamination with maternal blood from the placental compartment, indicate that traversal of the placental barrier by Pf-iE occurs in a proportion of cases, seemingly dependent on geographical location. This is best illustrated by the fact that the same group of researchers has consistently observed 1–3% of cord blood

Dendritic cells

There are no published studies dealing specifically with neonatal dendritic cells and possible PAM-induced functional changes. At the purely descriptive level, absolute numbers of both myeloid and plasmacytoid DC are increased in cord blood of those whose mothers experienced Pf infection during gestation [88], but any functional implication of this observation remains to be determined. Interestingly, in the same study, a significant inverse association, independent of the presence or absence of

Neonatal acquired immunity: T cells & PAM

A handful of cross-sectional studies performed in the last decade have assessed the capacity of neonatal (cord blood) T cells to respond to in vitro stimulation with Pf antigens (Table 1). Cameroonian neonates’ cord blood mononuclear cells (CBMC) produced less IFN-γ than adults’ cells but similar amounts of other cytokines (IL-2, IL-4), although the overall levels of lymphoproliferative and cytokine responses were low and PAM was found to be associated only with elevated Pf asexual stage

Cytokines, chemokines & PAM

PAM skews the placental environment from the normal Th2-type [66] to a Th1-type cytokine milieu, with a majority of the relevant studies revealing increased levels of TNF-α in the placental compartment [62], [67], [68], [69], [70], [71], [72]. Semi-mature DC can develop when immature DC are exposed to TNF-α in the absence of a pathogenic motif, and the impaired capacity of such DC to stimulate T cells leads to generation of regulatory T cells (Treg) [73], [74]. Immature foetal DC may thus be

Immunology meets epidemiology and public health

The results of two recent studies, although still requiring confirmation by others, seem set to alter our thinking about placental Pf infection and its influence on encounter with the parasite in early life. Firstly, the epidemiological observation that offspring of Pf-infected primigravid mothers are at significantly lower risk of parasitaemia during infancy than those born either to Pf-infected multigravid or to uninfected primigravid mothers challenges the expectation that PAM must always

Acknowledgements

The invaluable contributions of our many friends and colleagues cannot be overstated. In particular we recognize the pivotal support and advice of Urszula Krzych and Peter G. Kremsner. Our own work relied heavily on the willing participation of mothers and their babies, for which we are grateful, and on the help of a multitude of staff at the Albert Schweitzer Hospital in Lambaréné and the Medical Research Unit thereof, to all of whom we are thankful.

References (89)

  • G. Krishnegowda et al.

    Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity

    J Biol Chem

    (2005)
  • M. Walther et al.

    Upregulation of TGF-beta, FOXP3, and CD4 + CD25 + regulatory T cells correlates with more rapid parasite growth in human malaria infection

    Immunity

    (2005)
  • R. Raghupathy

    Th1-type immunity is incompatible with successful pregnancy

    Immunol Today

    (1997)
  • H.H. Smits et al.

    Different faces of regulatory DCs in homeostasis and immunity

    Trends Immunol

    (2005)
  • M.K. Levings et al.

    Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25 + CD4 + Tr cells

    Blood

    (2005)
  • K. Steinbrink et al.

    CD4(+) and CD8(+) anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity

    Blood

    (2002)
  • J. Hill et al.

    Insecticide-treated nets

    Adv Parasitol

    (2006)
  • L. Hviid

    The immuno-epidemiology of pregnancy-associated malaria: a variant surface antigen-specific perspective

    Parasite Immunol

    (2004)
  • J.G. Beeson et al.

    The immunology and pathogenesis of malaria during pregnancy

    Curr Top Microbiol Immunol

    (2005)
  • P.E. Duffy et al.

    Malaria in pregnancy: deadly parasite, susceptible host

    (2001)
  • R.W. Steketee et al.

    The burden of malaria in pregnancy in malaria-endemic areas

    Am J Trop Med Hyg

    (2001)
  • J.Y. Le Hesran et al.

    Maternal placental infection with Plasmodium falciparum and malaria morbidity during the first 2 years of life

    Am J Epidemiol

    (1997)
  • M. Cot et al.

    Maternally transmitted antibodies to pregnancy-associated variant antigens on the surface of erythrocytes infected with Plasmodium falciparum: relation to child susceptibility to malaria

    Am J Epidemiol

    (2003)
  • T.K. Mutabingwa et al.

    Maternal malaria and gravidity interact to modify infant susceptibility to malaria

    PLoS Med

    (2005)
  • R.S. Desowitz

    Prenatal immune priming in malaria: antigen-specific blastogenesis of cord blood lymphocytes from neonates born in a setting of holoendemic malaria

    Ann Trop Med Parasitol

    (1988)
  • F.N. Rasheed et al.

    Relationships between maternal malaria and malarial immune responses in mothers and neonates

    Parasite Immunol

    (1995)
  • N. Fievet et al.

    Malaria cellular immune responses in neonates from Cameroon

    Parasite Immunol

    (1996)
  • C.L. King et al.

    Acquired immune responses to Plasmodium falciparum merozoite surface protein-1 in the human fetus

    J Immunol

    (2002)
  • K. Brustoski et al.

    IFN-gamma and IL-10 mediate parasite-specific immune responses of cord blood cells induced by pregnancy-associated Plasmodium falciparum malaria

    J Immunol

    (2005)
  • K. Brustoski et al.

    Neonatal and maternal immunological responses to conserved epitopes within the DBL-gamma3 chondroitin sulfate A-binding domain of Plasmodium falciparum erythrocyte membrane protein 1

    Infect Immun

    (2005)
  • I. Malhotra et al.

    Distinct Th1- and Th2-type prenatal cytokine responses to Plasmodium falciparum erythrocyte invasion ligands

    Infect Immun

    (2005)
  • K. Brustoski et al.

    Reduced cord blood immune effector-cell responsiveness mediated by CD4+ cells induced in utero as a consequence of placental Plasmodium falciparum infection

    J Infect Dis

    (2006)
  • E.A. Achidi et al.

    Antibodies to Pf155/RESA and circumsporozoite protein of Plasmodium falciparum in paired maternal-cord sera from Nigeria

    Parasite Immunol

    (1995)
  • I. Malhotra et al.

    Influence of maternal filariasis on childhood infection and immunity to Wuchereria bancrofti in Kenya

    Infect Immun

    (2003)
  • I. Malhotra et al.

    Prenatal T cell immunity to Wuchereria bancrofti and its effect on filarial immunity and infection susceptibility during childhood

    J Infect Dis

    (2006)
  • I. Malhotra et al.

    Helminth- and Bacillus Calmette-Guerin-induced immunity in children sensitized in utero to filariasis and schistosomiasis

    J Immunol

    (1999)
  • P.T. Soboslay et al.

    Prenatal immune priming in onchocerciasis-Onchocerca volvulus-specific cellular responsiveness and cytokine production in newborns from infected mothers

    Clin Exp Immunol

    (1999)
  • S. Fadel et al.

    Cellular immune responses in neonates

    Int Rev Immunol

    (2000)
  • A.M. Garcia et al.

    T cell immunity in neonates

    Immunol Res

    (2000)
  • J.P. Ridge et al.

    Neonatal tolerance revisited: turning on newborn T cells with dendritic cells

    Science

    (1996)
  • E. Rainsford et al.

    Interleukin 10, produced in abundance by human newborn T cells, may be the regulator of increased tolerance associated with cord blood stem cell transplantation

    Br J Haematol

    (2002)
  • P. Han et al.

    Potential immaturity of the T-cell and antigen-presenting cell interaction in cord blood with particular emphasis on the CD40-CD40 ligand costimulatory pathway

    Immunology

    (2004)
  • H. Jonuleit et al.

    Induction of interleukin 10-producing, non-proliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells

    J Exp Med

    (2000)
  • S.C. Redd et al.

    Transplacental transmission of Plasmodium falciparum in rural Malawi

    Am J Trop Med Hyg

    (1996)
  • Cited by (59)

    • Impact of maternally derived antibodies to Plasmodium falciparum Schizont Egress Antigen-1 on the endogenous production of anti-PfSEA-1 in offspring

      2019, Vaccine
      Citation Excerpt :

      Immune responses to a number of antigens have been evaluated in mother-infant pairs in the context of placental malaria or malaria in pregnancy [17–22]. While several have focused on the impact of placental malaria on malaria outcomes during infancy [2–4,6,23], few studies have investigated the influence of maternal antibodies on infant antibody acquisition. P. falciparum Schizont Egress Antigen-1 (PfSEA-1) has emerged as a promising vaccine candidate antigen.

    • Early-life T-helper 1 immunity

      2020, Critical Reviews in Immunology
    • The immune response to malaria in utero

      2020, Immunological Reviews
    View all citing articles on Scopus
    View full text