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  • Commentary
  • Open Access
  • Open Peer Review

How does malaria in pregnancy impact malaria risk in infants?

BMC Medicine201816:212

https://doi.org/10.1186/s12916-018-1210-8

  • Received: 10 October 2018
  • Accepted: 6 November 2018
  • Published:

The original article was published in BMC Medicine 2018 16:198

Open Peer Review reports

Abstract

Malaria in pregnancy not only exerts profound negative consequences on the health of the mother and developing fetus, but may also alter the risk of malaria during infancy. Although mechanisms driving this altered risk remain unclear, in utero exposure to malaria antigens may impact the development of fetal and infant innate immunity. In an article in BMC Medicine, Natama et al. describe an ambitious analysis of basal and TLR-stimulated cord blood responses among a birth cohort in Burkina Faso. Basal levels of several cytokines, chemokines, and growth factors were shown to be significantly lower in cord blood with histopathologic evidence of placental malaria. Additionally, following TLR7/8 stimulation, samples obtained from infants of mothers with placental malaria were hyper-responsive compared to those without evidence of prenatal malaria exposure. Furthermore, several responses impacted by placental malaria were associated with differential malaria risk in infancy. Understanding how malaria in pregnancy shapes immune responses in infants will provide critical insight into the rational design of malaria control strategies during pregnancy, including intermittent preventative treatment in pregnancy and vaccines.

Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1187-3

Keywords

  • Malaria
  • innate immunity
  • malaria in pregnancy
  • cord blood
  • TLR stimulation

Background

Malaria in pregnancy remains a significant problem across sub-Saharan Africa, exerting profound negative consequences on the health of the mother and developing fetus [1]. Additionally, there is increasing evidence that malaria exposure in utero may alter the risk of malaria and non-malarial febrile infections in infancy, with studies showing that offspring of women who experience malaria in pregnancy are at increased risk of malaria themselves [25]. However, it remains unclear whether these associations are a direct result of malaria in pregnancy or rather reflect shared environmental exposures between maternal–infant pairs.

The use of multiple definitions of malaria exposure during pregnancy complicates the evaluation of the impact of such exposure on infancy. Although Plasmodium falciparum infection in pregnancy can be detected in maternal peripheral blood, it is also sequestered in the placenta through binding to chondroitin sulfate A expressed on the placental syncytiotrophoblast via the parasite molecule VAR2CSA [6, 7]. Importantly, not all women with P. falciparum infection detected in peripheral blood have evidence of placental malaria [8], and these overlapping definitions of malaria exposure in pregnancy may exert differential impacts on the developing fetus.. Further, several strategies for diagnosing placental malaria can be utilized, including assessment of placental blood to detect parasites and histopathologic evaluation to detect parasites, hemozoin pigment, or both. Identification and classification of these pathologic findings as either active infection (detection of parasites with (acute) or without (chronic) hemozoin) versus past infection (detection of hemozoin pigment alone) has been associated with differential impacts on infant outcomes, including adverse birth outcomes such as preterm birth [6, 911].

Although there are several potential mechanisms by which maternal malaria may impact the risk of malaria in infancy, it is increasingly appreciated that malaria in pregnancy may directly impact the development of the fetal and infant immune system [12, 13]. However, the precise mechanisms by which malaria in pregnancy may impact the risk of malaria in infancy remain elusive. Furthermore, it remains unclear whether alterations in fetal and infant immunity induced by malaria in pregnancy are then causally responsible for alterations in malaria risk in infants.

Impact of malaria in pregnancy on innate immune responsivity in infants

Several studies have investigated the effect of malaria in pregnancy on innate immune responses in the neonate, particularly focusing on the activation of antigen presenting cells following stimulation with toll like receptor (TLR) ligands [1416]. These studies have tested the hypothesis that in utero malaria antigen exposure may drive abnormal antigen presenting cell activation, leading to parasite-specific tolerance and an increased risk of infection in infants. Stimulation with polyinosinic-polycytidylic acid (TLR3), LPS (TLR4), and/or CpG oligonucleotide type A (TLR9) has been associated with altered cytokine production in whole cord blood [16] or cord blood mononuclear cells [14, 15] isolated from infants born to mothers exposed to malaria in pregnancy. Furthermore, increased cord blood production of IL-10 after TLR3 or TLR7/8 (resiquimod) stimulation was associated with an increased risk of P. falciparum infection during infancy [16], suggesting clinical consequences of differential TLR signaling at birth. However, these studies were limited by the panel of cytokines tested, as well as by the varying (and non-specific) definitions of malaria exposure in pregnancy.

Natama et al. [17] undertook an ambitious analysis of cord blood innate cell responsivity to TLR stimulation among a well-characterized birth cohort in a highly malaria endemic setting in Burkina Faso, posing two overarching questions. Firstly, what impact do different manifestations of malaria in pregnancy have on a broad panel of cytokines, chemokines, and growth factors measured at birth, both at baseline and following TLR-stimulation? Secondly, is basal or TLR-stimulated cytokine production at birth associated with protection from malaria in infancy? The study involved cord blood obtained from 313 maternal–infant pairs enrolled in a clinical trial in Burkina Faso assessing novel interventions to prevent malaria in pregnancy [18]. In this trial, pregnant women were enrolled and followed by both active and passive surveillance for malaria infection during pregnancy; at delivery, placental tissue was examined for histopathologic evidence of placental malaria as defined above. Infants born to these mothers were followed through 1 year of age. Natama et al. [17] assayed a panel of 30 cytokines, chemokines, and growth factors in whole cord blood supernatants by Luminex following stimulation with TLR3, 7/8, and 9 agonists, or unstimulated controls. The authors first looked for associations between malaria exposure in pregnancy and these immune features, and then evaluated whether basal or TLR-stimulated immune profiles at birth were associated with differential malaria risk in the first year of life. Basal levels of several immune features, including cytokines (e.g., IFN-α, IL-1β, IL-1RA, TNF, IFN-γ, IL-10), chemokines (e.g., MIP-1α, Rantes), and growth factors (e.g., G-CSF, GM-CSF, FGF), were found to be significantly lower in samples with evidence of malaria in pregnancy than in those that were unexposed. However, cord blood samples obtained from infants with evidence of ‘past’ placental malaria showed increased responsivity to TLR7/8 stimulation.

One potential explanation for these results is the possibility of differential admixture of cells in cord blood from infants exposed to malaria in utero, though cord blood cellular populations were not measured in this study. Indeed, malaria in pregnancy has been associated with increased myeloid dendritic cells in cord blood [19, 20] and malaria pigment in the placenta has also been associated with ‘partial maturation’ of cord blood myeloid and plasmacytoid dendritic cells [15]. However, an alternative explanation is that malaria exposure in pregnancy may alter innate cell responsivity, including the possibility that malaria exposure may induce ‘trained’ innate immunity, as has recently been suggested [21], though this remains to be determined.

Importantly, the authors found that several immunologic features impacted by placental malaria exposure were also associated with differential malaria risk in infancy. For example, higher concentrations of GM-CSF and eotaxin following TLR7/8 stimulation, of IL-1β following TLR9 stimulation, and of IL-7 following IL-3 stimulation, were associated with an increased hazard of malaria in the first year of life. In contrast, a higher concentration of IP-10 following TLR3 or TLR9 stimulation was associated with a lower hazard of malaria. Taken together, these data suggest that placental malaria may influence cord blood responsivity, and that these alterations may impact the subsequent risk of malaria early in life.

Conclusion

Malaria during pregnancy may lead to significant and long-lasting effects on the infant, including a predisposition to a greater risk of malaria in early life. By finding that placental malaria may impact innate immune responsivity in infants, and that these alterations may be associated with differential malaria risk in infants, Natama et al. [17] suggest a potential mechanism for this epidemiologic association. Future studies will need to evaluate whether (and how) malaria in pregnancy may perturb innate cellular populations, including whether placental malaria may drive intrinsic changes within these cells. Furthermore, mechanistic studies should attempt to determine whether these immunologic correlates are causally responsible for the associations observed. An improved understanding of how malaria in pregnancy shapes immune responses in infants may provide important insights into the rational design and development of malaria control strategies in pregnancy.

Declarations

Funding

No dedicated funding was required for preparation of the Commentary.

Author’s contributions

Dr. Jagannathan wrote and approved the final manuscript.

Ethics approval

Not applicable.

Competing interests

The author declares that he has no competing interests.

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Authors’ Affiliations

(1)
Department of Medicine, Stanford University, Stanford, USA

References

  1. Walker PG, ter Kuile FO, Garske T, Menendez C, Ghani AC. Estimated risk of placental infection and low birthweight attributable to Plasmodium falciparum malaria in Africa in 2010: a modelling study. Lancet Glob Health. 2014;2(8):e460–7.View ArticleGoogle Scholar
  2. Le Hesran JY, Cot M, Personne P, Fievet N, Dubois B, Beyeme M, Boudin C, Deloron P. Maternal placental infection with Plasmodium falciparum and malaria morbidity during the first 2 years of life. Am J Epidemiol. 1997;146(10):826–31.View ArticleGoogle Scholar
  3. Mutabingwa TK, Bolla MC, Li JL, Domingo GJ, Li X, Fried M, Duffy PE. Maternal malaria and gravidity interact to modify infant susceptibility to malaria. PLoS Med. 2005;2(12):e407.View ArticleGoogle Scholar
  4. Schwarz NG, Adegnika AA, Breitling LP, Gabor J, Agnandji ST, Newman RD, Lell B, Issifou S, Yazdanbakhsh M, Luty AJ, et al. Placental malaria increases malaria risk in the first 30 months of life. Clin Infect Dis. 2008;47(8):1017–25.View ArticleGoogle Scholar
  5. Bardaji A, Sigauque B, Sanz S, Maixenchs M, Ordi J, Aponte JJ, Mabunda S, Alonso PL, Menendez C. Impact of malaria at the end of pregnancy on infant mortality and morbidity. J Infect Dis. 2011;203(5):691–9.View ArticleGoogle Scholar
  6. Brabin BJ, Romagosa C, Abdelgalil S, Menendez C, Verhoeff FH, McGready R, Fletcher KA, Owens S, D'Alessandro U, Nosten F, et al. The sick placenta-the role of malaria. Placenta. 2004;25(5):359–78.View ArticleGoogle Scholar
  7. Fried M, Duffy PE. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science. 1996;272(5267):1502–4.View ArticleGoogle Scholar
  8. Boudova S, Divala T, Mungwira R, Mawindo P, Tomoka T, Laufer MK. Placental but Not Peripheral Plasmodium falciparum Infection During Pregnancy Is Associated With Increased Risk of Malaria in Infancy. J Infect Dis. 2017;216(6):732–5.View ArticleGoogle Scholar
  9. Rogerson SJ, Hviid L, Duffy PE, Leke RF, Taylor DW. Malaria in pregnancy: pathogenesis and immunity. Lancet Infect Dis. 2007;7(2):105–17.View ArticleGoogle Scholar
  10. Kapisi J, Kakuru A, Jagannathan P, Muhindo MK, Natureeba P, Awori P, Nakalembe M, Ssekitoleko R, Olwoch P, Ategeka J, et al. Relationships between infection with Plasmodium falciparum during pregnancy, measures of placental malaria, and adverse birth outcomes. Malar J. 2017;16(1):400.View ArticleGoogle Scholar
  11. Muehlenbachs A, Fried M, McGready R, Harrington WE, Mutabingwa TK, Nosten F, Duffy PE. A novel histological grading scheme for placental malaria applied in areas of high and low malaria transmission. J Infect Dis. 2010;202(10):1608–16.View ArticleGoogle Scholar
  12. Harrington WE, Kakuru A, Jagannathan P. Malaria in pregnancy shapes the development of foetal and infant immunity. Parasite Immunol. 2018:e12573. https://doi.org/10.1111/pim.12573. Epub ahead of print.
  13. Odorizzi PM, Feeney ME. Impact of In Utero Exposure to Malaria on Fetal T Cell Immunity. Trends Mol Med. 2016;22(10):877–88.View ArticleGoogle Scholar
  14. Adegnika AA, Kohler C, Agnandji ST, Chai SK, Labuda L, Breitling LP, Schonkeren D, Weerdenburg E, Issifou S, Luty AJ, et al. Pregnancy-associated malaria affects toll-like receptor ligand-induced cytokine responses in cord blood. J Infect Dis. 2008;198(6):928–36.View ArticleGoogle Scholar
  15. Fievet N, Varani S, Ibitokou S, Briand V, Louis S, Perrin RX, Massougbogji A, Hosmalin A, Troye-Blomberg M, Deloron P. Plasmodium falciparum exposure in utero, maternal age and parity influence the innate activation of foetal antigen presenting cells. Malar J. 2009;8:251.View ArticleGoogle Scholar
  16. Gbedande K, Varani S, Ibitokou S, Houngbegnon P, Borgella S, Nouatin O, Ezinmegnon S, Adeothy AL, Cottrell G, Massougbodji A, et al. Malaria modifies neonatal and early-life toll-like receptor cytokine responses. Infect Immun. 2013;81(8):2686–96.View ArticleGoogle Scholar
  17. Natama H, Moncunill G, Rovira-Vallbona E, Sanz H, Sorgho H, Aguilar R, Coulibaly-Traore M, Some MA, Scott S, Valea I, et al. Modulation of innate immune responses at birth by prenatal malaria exposure and association with malaria risk during the first year of life. BMC Med. 2018;16(1):198.View ArticleGoogle Scholar
  18. COSMIC Consortium. Community-based Malaria Screening and Treatment for Pregnant Women Receiving Standard Intermittent Preventive Treatment With Sulfadoxine-Pyrimethamine: A Multicenter (The Gambia, Burkina Faso, and Benin) Cluster-randomized Controlled Trial. Clin Infect Dis. 2018. 10.1093/cid/ciy522. Epub ahead of print.
  19. Breitling LP, Fendel R, Mordmueller B, Adegnika AA, Kremsner PG, Luty AJ. Cord blood dendritic cell subsets in African newborns exposed to Plasmodium falciparum in utero. Infect Immun. 2006;74(10):5725–9.View ArticleGoogle Scholar
  20. Prahl M, Jagannathan P, McIntyre TI, Auma A, Farrington L, Wamala S, Nalubega M, Musinguzi K, Naluwu K, Sikyoma E, et al. Timing of in utero malaria exposure influences fetal CD4 T cell regulatory versus effector differentiation. Malar J. 2016;15(1):497.View ArticleGoogle Scholar
  21. Schrum JE, Crabtree JN, Dobbs KR, Kiritsy MC, Reed GW, Gazzinelli RT, Netea MG, Kazura JW, Dent AE, Fitzgerald KA, et al. Cutting Edge: Plasmodium falciparum Induces Trained Innate Immunity. J Immunol. 2018;200(4):1243–8.View ArticleGoogle Scholar

Copyright

© The Author(s). 2018

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