The pregnancy-associated secretome in malaria pathogenesis and immunity during gestation

Lucy Mwai; Paulus Adamba; Benjamin Mordmüller; Manu Vatish; Yoel Sadovsky; Jesse Gitaka; Francis M. Kobia; Bernard N. Kanoi

doi:10.12688/openreseurope.18351.1

The pregnancy-associated secretome in malaria pathogenesis and immunity during gestation

Lucy Mwai ,
Paulus Adamba ,
Benjamin Mordmüller ,
Manu Vatish
,
Yoel Sadovsky
,
Jesse Gitaka
,
Francis M. Kobia
,
Bernard N. Kanoi

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October 17, 2024

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https://doi.org/10.12688/openreseurope.18351.1

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October 17, 2024 (Published Manuscript Under Review 1.0)

Royal Society, Future Leaders African Independent Researchers (FLAIR) Scheme

Grant ID(s): FLR\R1\201314
European & Developing Countries Clinical Trials Partnership

Grant ID(s): TMA2020CDF3203
US National Institutes of Health

Grant ID(s): R01HD103727

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Placental malaria, pregnancy-associated secretome, Plasmodium falciparum, maternal physiology, sequestration

Abstract

In pregnancy, fetal health, growth and development are dependent on normal placental development. However, the mechanisms that support maternal immune tolerance for the fetus, fetal nourishment, and pregnancy maintenance to term are not fully understood. Placental secretions into the intervillous space play a key role in shaping early placental function. In their entirety, they represent the pregnancy-associated secretome (PAS). PAS alterations have been associated with various complications such as fetal growth restriction, maternal anemia, and preterm birth. Placental malaria (PM), caused by the sequestration of Plasmodium falciparum-infected erythrocytes in the intervillous space, affects PAS composition. In this review, we explore how P. falciparum-induced changes of PAS may contribute to pathogenesis and immune dysregulation during pregnancy, as well as the possibilities of leveraging PAS components as biomarkers for the prevention, diagnosis, and management of PM.

Corresponding author

Jesse Gitaka

jgitaka@mku.ac.ke

Grant information

This project has received funding from the European and Developing Countries Clinical Trials Partnership progamme under grant agreement number TMA2020CDF3203 EndPAMAL (to BNK). It was also supported by US National Institutes of Health grant number R01HD103727 (to YS), and the Royal Society, Future Leaders African Independent Researchers (FLAIR) Scheme number FLR\R1\201314 (to JG). The funding sources had no role in study design, collection, analysis, interpretation of data, and publication.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

© 2024 Lucy Mwai (Co-Author); Paulus Adamba (Co-Author); Benjamin Mordmüller (Co-Author); Manu Vatish (Co-Author); Yoel Sadovsky (Co-Author); Jesse Gitaka (Corresponding Author, Co-Author); Francis M. Kobia (Co-Author); Bernard N. Kanoi (Co-Author)

This work is licensed under a Creative Commons Attribution 4.0 International License.

First version published

October 17, 2024 (https://doi.org/10.12688/openreseurope.18351.1)

Latest version published

October 17, 2024 (https://doi.org/10.12688/openreseurope.18351.1)

Introduction

Malaria is caused by Plasmodium parasites, which are transmitted through the bites of infected female anopheline mosquitos. According to the World Health Organization, malaria causes >10,000 maternal deaths and >200,000 neonatal deaths annually¹, with most occurring in sub-Saharan Africa. Malaria in pregnancy (MiP) poses a significant threat to the mother and fetus because Plasmodium falciparum-infected red blood cells (iRBCs) can sequester in the placenta, causing placental malaria (PM)², which is associated with serious adverse outcomes, including maternal anemia, fetal growth restriction, preterm birth, stillbirth, and increased neonatal mortality³. Malaria parasite sequestration in the placenta is facilitated by variant surface chondroitin surface antigen 2 (VAR2CSA), a member of the P. falciparum membrane protein 1 (PfEMP1) family of proteins, which is mutually exclusively expressed on the surface of iRBCs⁴. The surface of the syncytiotrophoblast, the specialized outermost placental epithelial cell layer that is in direct contact with maternal blood⁵, contains VAR2CSA’s receptor, chondroitin sulfate A (CSA). Despite CSA being expressed on many cell types in the human host, VAR2CSA preferentially binds to chondroitin sulfate carrying 4-O-sulfation of the N-acetyl-D-Galactosamine (GalNAc) residues found in the placenta⁶. The interaction between VAR2CSA on the surface of iRBCs and CSA, facilitates the sequestration of iRBCs in the intervillous space, causing PM^6,7. Additionally, the upregulation of intercellular adhesion molecules (ICAMs), leads to a syncytium-like adhesion of iRBCs to endothelial walls, which impairs malaria parasite clearance as they evade splenic destruction contributing to the persistence of MiP⁴.

Embryo implantation, early growth and development, and adaptive changes in maternal physiology depend on the pregnancy-associated secretome (PAS) in the intervillous space (Figure 1). PAS has a complex composition including proteins, hormones, growth factors, antibodies, and immunomodulatory molecules like cytokines and chemokines⁸. PAS associated components, such as endometrial and uterine-derived cells express heat shock proteins (HSPs), including HSP27, HSP60, HSP70, and HSP90, which are abundant in the first trimester of pregnancy⁹ and are involved in decidualization, implantation, and placentation^9,10. Dysregulated expression of these HSPs has been associated with placental necrosis, implantation failure, and loss of pregnancy⁹. MiRNA-containing placenta-derived extracellular vesicles, which are released by the trophoblast cells into the uterine cavity, are another PAS component thought to facilitate fetal growth^11–13. In addition, secretions connected with Placenta-Associated Maternal Monocytes/Macrophages (PAMM1a) cells localize at sites of syncytium layer when damaged by infections to facilitate placental tissue repair¹⁴. Other PAS components are part of immune adaptations that are implicated in the prevention of fetal immunological rejection and the promotion of successful implantation^11,15, among them are immune mediators derived from T helper 1 and T helper 2 immune cells that promote fetal implantation and development, and regulatory T cells, which promote tolerance for paternal alloantigens^16–19.

Figure 1. Pregnancy-associated secretome (PAS) function during fetal growth and development.

(Image created with BioRender.com).

The intricate interaction between PAS components and placenta must be maintained throughout pregnancy and disruptions of this interaction cause implantation failure, fetal growth restriction, and preterm birth^8,20. Recent studies have implicated various P. falciparum-induced PAS-alterations in PM pathogenesis^19,21. In this review, we discuss the potential role of PAS components and their alterations in the pathogenesis of PM and immunity against PM, as well as their implications for PM diagnosis, prevention, and therapy.

The PAS components implicated in the pathogenesis of PM

P. falciparum infection during pregnancy has been shown to affect various PAS components. Following iRBCs sequestration in the intervillous space, tumor necrosis factor-alpha (TNF-α) and reactive oxygen species (hydrogen peroxide, the hydroxyl radical, and the superoxide anion) elevate oxidative stress^19,21,22. This causes monocyte and macrophage infiltration, which triggers placental apoptosis^18,19 and activates leukocytes²³, which drives further cytokine release. In addition, TNF-α-dependent monocyte recruitment can damage RBCs through oxidative stress or erythropoiesis inhibition²¹. Although TNF-α also attracts natural killer cells, which are beneficial in facilitating uterine vasculature adaptation to fetal demands for gas and nutrients at the maternal–fetal interface²⁴, high TNF-α levels can induce fetal necrosis¹⁷.

P. falciparum causes placental inflammation through several pathways. The main immune signaling pathways include the activation of interferon (IFN)-β and IFN-α (type I IFNs) and IFN-γ (type II IFN)²⁵. IFN-γ activates proinflammatory cytokines, chemokines, and growth factors, which are important for tissue regeneration and the clearance of intracellular pathogens²⁵. Overactivation of the IFN-γ pathway may damage placental tissues through excessive inflammation²⁵. Interleukin (IL)-10, an anti-inflammatory cytokine produced throughout pregnancy, along with the activation of IFN-β, counteracts this risk by attenuating IFN-γ overactivation²⁶. IL-10 suppresses pro-inflammatory responses by elevating type 1 regulatory cells and restricting antibody response during blood-stage infection²⁵. Further, IFN-α and TNF-α are produced by cytotoxic T lymphocytes, which are elevated in P. falciparum-infected placentas^19,27. Indeed, overactivation of placenta and cord blood cytokines have been shown to affect fetal birth weight²⁸. The overactivation of IFN-γ, TNF-α, IL-1β, IL-12p70, and IL-10 have been associated with reduced birth weight, whereas the overactivation of IL-28A (also known as IFN-L2/IFNλ2), IL-27, and IL-17E are associated with increased birth weight^27–29.

PM-induced chemokines, which accumulate in the intervillous space during iRBCs sequestration and mobilize monocytes, macrophages, cytotoxic T cells, granulocytes, and fetal and maternal B cells, are another important PAS component (Figure 2)^14,30. Their effects may cause intervillositis (prolonged inflammation in the intervillous space), which is associated with increased fibrin deposition and syncytial knotting, which are implicated in fetal growth restriction, miscarriage, and stillbirth^14,31. ICAM4 expression also increases the adhesion of PAMM1a to the syncytium via the expression of lymphocyte function-associated antigen-1, which drives further inflammation and may allow placental infection by opportunistic microbes¹⁴.

Figure 2. Activated immune components during PM.

The image shows the involvement of the pregnancy-associated secretome (PAS) in PM pathogenesis and immunity. (Image created with BioRender.com).

PM activates PAS components belonging to the complement system, which also activate innate immunity^32,33. This probably takes place via complement 3-independent pathways, specifically the cleavage of complements 3 and 5, mediated by thrombin and serine proteases from phagocytic leukocytes or possibly, by P. falciparum itself³⁴. Although this complement activation plays a critical role in neutralizing invading P. falciparum, excessive activation is associated with malaria exacerbation through overwhelming complement regulatory proteins, leading to adverse maternal and fetal outcomes³³.

Malaria parasites-specific components, such as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), are known to trigger immune responses through pathogen-recognition receptors (PRRs)³⁵, although they are not placenta-specific. For instance, the glycosylphosphatidylinositol (GPI) anchor, a molecule essential for parasite survival and immune activation^35,36 by facilitating key processes such as erythrocyte invasion, is a PAMP. GPI interacts with the host’s toll-like receptors (TLRs), particularly TLR2-TLR1, triggering signaling pathways like Mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). These pathways result in the production of pro-inflammatory cytokines, such as TNF-α and Interleukin (IL)-1³⁶, contributing to the systemic inflammation observed in malaria, which could also affect the placenta.

Immune response is further amplified by other malaria parasite components such as hemozoin (DAMP), lipid peroxides (PAMP), and parasite nucleic acids (PAMP)³⁵. Hemozoin, is a byproduct of hemoglobin digestion by the parasite that acts as a danger signal, activating the NOD-like receptor protein 3 (NLRP3) inflammasome and promoting the production of Interlukin (IL)-1β and other inflammatory mediators^37,38. Lipid peroxides, released during oxidative stress in malarial infection, also play a crucial role in immune activation, causing cellular damage and modulating immune cell activity, thereby sustaining the inflammatory environment^21,35. Furthermore, malaria parasite DNA and RNA are recognized by host pattern recognition receptors like cyclic GMP-AMP synthase (cGAS), leading to the activation of the stimulator of interferon genes (STING) pathway and the production of type I interferons and other cytokines, which amplify the immune response^35,39.

PAS-associated immunity during the peripartum and postpartum periods

Immunity to PM is mainly driven by the acquisition of anti-VAR2CSA antibodies, which can act through several mechanisms, including the blocking of iRBCs adherence to CSA by anti-VAR2CSA adhesion-blocking opsonic antibodies⁴⁰ and antibody-mediated effector functions through the activation of complement pathways against various stages of the parasite’s life cycle, which may clear parasites and contribute to acquired anti-malaria immunity (Figure 2)³³. Successive pregnancies are associated with the development of resistance to PM and unlike primigravida, women with multiple pregnancies have protective antibodies against P. falciparum antigens, such as anti-VAR2CSA antibodies, which might block iRBCs adherence to the placenta^41,42. These anti-VAR2CSA antibodies are being targeted in the development of placental malaria vaccines (PMV)⁴³. Thus far, there is no approved PMV for use in pregnant women, but two subunit vaccine candidates, namely the placental malaria vaccine (PAMVAC) based on interdomain region 1 through the duffy binding like domain 2 to interdomains 2 (ID1- DBL2X-ID2a) fragment, a 73-kDa derivative of the VAR2CSA from the P. falciparum FCR3 clone, and the Priming malaria vaccine (PRIMVAC) based on the DBL1X–DBL2X fragment, a 105-kDa derivative of the VAR2CSA from the 3D7 P. falciparum clone⁴³. The anti-VAR2CSA antibodies induced by these vaccines block parasite binding to CSA^44,45.

In response to malaria infection, recruited NK cells promote the onset of adaptive immunity through the clearance of P. falciparum iRBCs by natural cytotoxicity and antibody-dependent cellular cytotoxicity processes enhanced by the production of regulatory cytokines such as IFN-γ and TNF-α^46–49.

PM has been associated with the mobilization of monocytes and macrophages to the placenta⁵⁰. PAMM1a cells localize at sites of syncytium layer damage and contribute to placental tissue repair through the secretion of matrix metalloprotease-9 and fibronectin¹⁴. It is also hypothesized that PAMM1a contributes to placental protection against infection by potently responding to Toll-like receptor-mediated innate immune responses, which activate proinflammatory cytokines, chemokines and costimulatory molecules^14,50. Although evidence linking PM and PAMM1a is currently lacking, macrophages/monocytes have been found to infiltrate the placenta in response to hemozoin, the malarial pigment⁵¹. In response to PM, these phagocytic macrophages/monocytes are recruited by β and α chemokines, monocyte chemoattractant protein 1, macrophage-inflammatory protein 1α, interferon-inducible protein 10, and IL-8^26,52.

Little is known about the immunity to malaria and how it affects malaria pathogenesis in the postpartum period. A study done by Ramharter et al. showed that women have a 10-fold increased risk for developing malaria in the postpartum period due to factors like changes in immune responses and perinatally acquired infections postpartum, compared to control non-pregnant women who had not delivered within the last 6 months^53,54. Interestingly, there is evidence that Pf VAR2CSA specific IgG secretory B cell are maintained beyond birth⁵⁴. Data suggest that more than 40% of women who had not been pregnant for 1–6 years were seropositive to Pf VAR2CSA, indicating prolonged antibody immunity⁵⁵.

Conclusion and future perspectives

The dysregulation of PAS components during PM can negatively impact pregnant women, who are at elevated risk to experience severe malaria and have serious consequences for the fetus, including fetal growth restriction, preterm birth, and stillbirth. Thus, strategies that modulate PAS components may offer critical avenues for mitigating such adverse outcomes and improving pregnancy outcomes in high-risk areas.

Currently, diagnosing placental malaria (PM) is challenging because the gold standard test requires histological examination of placental tissue after delivery⁵⁶. Additionally, since PM may be present even in a pregnant woman with almost no peripheral parasitemia, malaria parasite detection based on microscopy the gold standard test as well as rapid diagnostic tests, have decreased sensitivity as most parasites are sequestrated⁵⁷. This argues for the development of tests that specifically detect PM and are less invasive than placental biopsy. Leveraging emerging strategies such as liquid biopsies (during pregnancy)⁵⁸ has a possibility of identifying early infections. Placenta liquid biopsies also represent a promising, non-invasive approach to analyze maternal blood for PAS components that may provide crucial insights into placental health in the presence of Plasmodium parasites.

Other promising approaches include the noninvasive prenatal testing (NIPT) and the analysis of extracellular vesicles (EVs), which carry placental molecular signatures^59,60. Integrating these methods with a deeper understanding of the pregnancy-associated secretome will enhance our ability to combat the complex challenges posed by P. falciparum during gestation, ultimately improving maternal and fetal health. These approaches may as well provide valuable insights into potential therapeutic avenues. For instance, it has been shown that treating necrotizing enterocolitis, a neonatal disease with considerably high morbidity and mortality, with ST266, an amnion-derived multipotent PAS component thought to upregulate critical genes during gut remodeling, can prevent early pregnancy loss^11,61.

Encouragingly, the two promising placental malaria vaccines named previously; PAMVAC and PRIMVAC prevent Plasmodium malaria parasite sequestration^43,62. These PM vaccine candidates underwent first-in-human, trials in Germany and Benin (PAMVAC)⁴⁵, France and Burkina Faso (PRIMVAC). Both candidates showed increased anti-VAR2CSA antibodies^41,63 that prevented Plasmodium parasite sequestration in an in vitro assay, offering a strategy for reducing PM prevalence and severity, although immunogenicity and breadth of protection was not optimal. Currently, a European Union funded project is aimed at improving the two vaccine candidates and performing Phase 1 and 2 studies⁶⁴. At the moment, the main interventional tool to improve pregnancy outcomes is intermittent preventive treatment in pregnant women (IPTp). It has been implemented to prevent P. falciparum infection in most highly malaria-endemic regions^65,66. When paired with education on mosquito bite prevention, it can enhance the efficacy of malaria infection prevention¹. However, the effectiveness of chemoprophylaxis is at risk of increasing parasite resistance to sulfadoxine–pyrimethamine, which is recommended by the World Health Organization for malaria prophylaxis in pregnant women⁶⁶.

In summary, future research should focus on developing specific biomarkers for PM diagnosis, understanding the role of PAS components in mediating maternal-fetal immune responses, and exploring the therapeutic potential of PAS-based interventions to improve maternal and child health in malaria-endemic regions.

Data availability statement

No data are associated with this article.

Author contributions

All authors have made substantial, direct, and intellectual contributions to the work. All authors approved the manuscript for publication.

Faculty Opinions recommended

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61. Sodhi CP, Ahmad R, Jia H, et al.: The administration of amnion-derived multipotent cell secretome ST266 protects against necrotizing enterocolitis in mice and piglets. Am J Physiol Gastrointest Liver Physiol. 2022; 323(3): G265–G282. PubMed Abstract | Publisher Full Text | Free Full Text
62. Nielsen MA, Staalsoe T, Kurtzhals JAL, et al.: Plasmodium falciparum variant surface antigen expression varies between isolates causing severe and nonsevere malaria and is modified by acquired immunity. J Immunol. 2002; 168(7): 3444–50. PubMed Abstract | Publisher Full Text
63. Salamanca DR, Gómez M, Camargo A, et al.: Plasmodium falciparum blood stage antimalarial vaccines: an analysis of ongoing clinical trials and new perspectives related to synthetic vaccines. Front Microbiol. 2019; 10: 2712. PubMed Abstract | Publisher Full Text | Free Full Text
64. European Vaccine Initiative: HOME Advance Vac4pm. 2023; [cited 2024 May 21]. Reference Source
65. WHO: WHO Guidelines for malaria. Who, June 2022; 210, [cited 2024 May 21]. Reference Source
66. World Health Organization: Updated WHO recommendations for malaria chemoprevention among children and pregnant women. World Health Organization, 2022; 2(1): 1–13. Reference Source

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October 17, 2024

DOI

https://doi.org/10.12688/openreseurope.18351.1

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October 17, 2024 (Published Manuscript Under Review 1.0)

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Royal Society, Future Leaders African Independent Researchers (FLAIR) Scheme

Grant ID(s): FLR\R1\201314
European & Developing Countries Clinical Trials Partnership

Grant ID(s): TMA2020CDF3203
US National Institutes of Health

Grant ID(s): R01HD103727

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Keywords

Placental malaria, pregnancy-associated secretome, Plasmodium falciparum, maternal physiology, sequestration

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Lucy Mwai

Centre for Malaria Elimination, Institute of Tropical Medicine, Mount Kenya University, Thika, Kiambu County, Kenya

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Co-Author, Formal Analysis, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

0000-0002-4983-5733

luciemgichuki@gmail.com

Paulus Adamba

Centre for Malaria Elimination, Institute of Tropical Medicine, Mount Kenya University, Thika, Kiambu County, Kenya

Department of Health service, KCA University, Nairobi, Nairobi County, Kenya

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Co-Author, Formal Analysis, Writing – Original Draft Preparation

0000-0002-1518-6309

pauladamba16@gmail.com

Benjamin Mordmüller

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Nijmegen, Gelderland, The Netherlands

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Co-Author, Writing – Review & Editing

0000-0001-9101-2768

benjamin.mordmueller@radboudumc.nl

Manu Vatish

Nuffield Department of Women’s & Reproductive Health, University of Oxford, United Kingdom, UK

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Co-Author, Validation, Writing – Review & Editing

manu.vatish@wrh.ox.ac.uk

Yoel Sadovsky

Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, USA

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Co-Author, Conceptualization, Funding Acquisition, Writing – Review & Editing

ysadovsky@mwri.magee.edu

Jesse Gitaka

Centre for Malaria Elimination, Institute of Tropical Medicine, Mount Kenya University, Thika, Kiambu County, Kenya

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Corresponding Author, Co-Author, Conceptualization, Funding Acquisition, Writing – Review & Editing

jgitaka@mku.ac.ke

Francis M. Kobia

Centre for Malaria Elimination, Institute of Tropical Medicine, Mount Kenya University, Thika, Kiambu County, Kenya

Roles

Co-Author, Formal Analysis, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing

kobiafrancis@gmail.com

Bernard N. Kanoi

Centre for Malaria Elimination, Institute of Tropical Medicine, Mount Kenya University, Thika, Kiambu County, Kenya

Roles

Co-Author, Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Resources, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

0000-0003-2772-7579

bkanoi@mku.ac.ke

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[59] 59. Han D, Li R, Shi J, et al.: Liquid biopsy for infectious diseases: a focus on microbial cell-free DNA sequencing. Theranostics. 2020; 10(12): 5501–5513. PubMed Abstract | Publisher Full Text | Free Full Text

[60] 60. Chaemsaithong P, Luewan S, Taweevisit M, et al.: Placenta-derived extracellular vesicles in pregnancy complications and prospects on a liquid biopsy for hemoglobin Bart’s disease. Int J Mol Sci. 2023; 24(6): 5658. PubMed Abstract | Publisher Full Text | Free Full Text

[61] 61. Sodhi CP, Ahmad R, Jia H, et al.: The administration of amnion-derived multipotent cell secretome ST266 protects against necrotizing enterocolitis in mice and piglets. Am J Physiol Gastrointest Liver Physiol. 2022; 323(3): G265–G282. PubMed Abstract | Publisher Full Text | Free Full Text

[62] 62. Nielsen MA, Staalsoe T, Kurtzhals JAL, et al.: Plasmodium falciparum variant surface antigen expression varies between isolates causing severe and nonsevere malaria and is modified by acquired immunity. J Immunol. 2002; 168(7): 3444–50. PubMed Abstract | Publisher Full Text

[63] 63. Salamanca DR, Gómez M, Camargo A, et al.: Plasmodium falciparum blood stage antimalarial vaccines: an analysis of ongoing clinical trials and new perspectives related to synthetic vaccines. Front Microbiol. 2019; 10: 2712. PubMed Abstract | Publisher Full Text | Free Full Text

[64] 64. European Vaccine Initiative: HOME Advance Vac4pm. 2023; [cited 2024 May 21]. Reference Source

[65] 65. WHO: WHO Guidelines for malaria. Who, June 2022; 210, [cited 2024 May 21]. Reference Source

[66] 66. World Health Organization: Updated WHO recommendations for malaria chemoprevention among children and pregnant women. World Health Organization, 2022; 2(1): 1–13. Reference Source

The pregnancy-associated secretome in malaria pathogenesis and immunity during gestation

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Lucy Mwai

Paulus Adamba

Benjamin Mordmüller

Manu Vatish

Yoel Sadovsky

Jesse Gitaka

Francis M. Kobia

Bernard N. Kanoi

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