Impact of In Utero Exposure to Malaria on Fetal T Cell Immunity

Abstract

Pregnancy-associated malaria, including placental malaria, causes significant morbidity and mortality worldwide. Recently, it has been suggested that in utero exposure of the fetus to malaria antigens may negatively impact the developing immune system and result in tolerance to malaria. Here, we review our current knowledge of fetal immunity to malaria, focusing on the dynamic interactions between maternal malaria infection, placental development and the fetal immune system. A better understanding of the long-term impact of in utero malaria exposure on the development of natural immunity to malaria, immune responses to other childhood pathogens, and vaccine immunogenicity is urgently needed. This may guide the implementation of novel chemoprevention strategies during pregnancy and facilitate the push towards malaria vaccines. KeywordsPlacental Malaria; Pregnancy-associated malaria; Fetal Immune System; Fetal Tolerance Global Impact of Pregnancy-Associated MalariaMalaria (see Glossary) remains one of the leading causes of morbidity and mortality worldwide, resulting in an estimated 500,000 deaths each year [1,2]. Pregnant women, infants and young children are the most vulnerable populations and account for the majority of infections. More than 125 million pregnancies occur annually in regions at risk for malaria transmission and one in four pregnant women in sub-Saharan Africa have evidence of malaria infection at parturition [1,2]. Moreover, pregnant women are at a greater risk for malaria infection relative to non-pregnant adults, experiencing higher levels of parasitemia and symptomatic disease [3,4]. Pregnancy-associated malaria, including placental malaria (PM), can have profound consequences on the developing fetus, leading to intrauterine growth retardation (IUGR), low birth weight (LBW), prematurity, miscarriage, and stillbirth [1,5].Corresponding author contact Information: margaret.feeney@ucsf.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptInfants and young children are highly susceptible to malaria during the first few years of life. In 2015, approximately 300,000 children under the age of five succumbed to malaria, with the highest mortality rates occurring in Africa [2]. Several epidemiological studies have found that the incidence of malaria during infancy and childhood is even higher among infants born to mothers with PM [6][7][8]. While this may partly due to the fact that infants of highly-exposed mothers are themselves at greater risk of environmental exposure, ...

Hyperparasitaemia during clinical malaria episodes in infants aged 0–24 months and its association with in utero exposure to Plasmodium falciparum

“…The findings of this study of hyperparasitaemia in infants prenatally exposed to P. falciparum may suggest inappropriate anti parasitic protective immunity. This suggestion is supported by observations from previous studies indicating that prenatal exposure to P. falciparum affected development of fetal regulatory and effector T cell responses [ 14 , 15 ]. The effect of prenatal exposure to P. falciparum on fetal immune cells may persist to childhood; leading to inappropriate anti-parasitic immunity and failure of effective immune response to control parasite replication during clinical malaria episodes, with subsequent hyperparasitaemia.…”

Placental Malaria

“…Further investigations regarding their safety and efficacy, also considering population dependent variances in protectivity, need to be conducted. Additionally, an interesting new area of research is the recently reviewed fetal in utero immune response against malaria, its effect during childhood, and differences based on sex [22,30].…”

“…It has been shown that histopathological changes and placental malaria enhance the risk of preeclampsia in pregnant women, especially in primigravidas [29]. Histopathological changes during placental malaria include presence of hemozoin, perivillous fibrin deposition [30,31], syncytial knot formation [32], and decrease in villous surface area (Fig. 2).…”

Immune effector mechanisms in malaria: An update focusing on human immunity

“…Pregnant women are at an increased of placental P. falciparum infections, the scope of which can be found reviewed elsewhere . Relevant to this review is the consideration of localized immune modifications during antenatal infections that could impact an infant's ability to mount a protective immune response to malaria . Pregnancy‐associated malaria studies highlight the concept that humans may not be immunologically naïve, even at birth, which could be an effect modifier when interpreting the function of immune mediators during early childhood.…”