Complement Activation and the Resulting Placental Vascular Insufficiency Drives Fetal Growth Restriction Associated with Placental Malaria

Abstract

Placental malaria (PM) is a major cause of fetal growth restriction, yet the underlying mechanism is unclear. Complement C5a and C5a receptor levels are increased with PM. C5a is implicated in fetal growth restriction in non-infection-based animal models. In a case-control study of 492 pregnant Malawian women, we find that elevated C5a levels are associated with an increased risk of delivering a small-for-gestational-age infant. C5a was significantly increased in PM and was negatively correlated with the angiogenic factor angiopoietin-1 and positively correlated with angiopoietin-2, soluble endoglin, and vascular endothelial growth factor. Genetic or pharmacological blockade of C5a or its receptor in a mouse model of PM resulted in greater fetoplacental vessel development, reduced placental vascular resistance, and improved fetal growth and survival. These data suggest that C5a drives fetal growth restriction in PM through dysregulation of angiogenic factors essential for placental vascular remodeling resulting in placental vascular insufficiency.

Functional Roles for C5a and C5aR but Not C5L2 in the Pathogenesis of Human and Experimental Cerebral Malaria

“…This hypothesis is supported by our data from the present and previous in vitro and in vivo studies (17,25) and by observations in human CM (5, 8-10, 17, 34, 43, 45, 46, 52). Furthermore, our observations are consistent with a growing body of compelling evidence implicating a causal role for C5a-C5aR in the induction of proinflammatory mediators and antiangiogenic factors in multiple disease conditions that share features with cerebral malaria, including sepsis, ischemia-reperfusion injuries, pathological angiogenesis, and neurocognitive and neurodegenerative disorders and most recently in studies of human and experimental placental malaria demonstrating a causal role for C5a-C5aR in altering placental angiogenesis and mediating adverse birth outcomes associated with malaria infection (19,22,60).…”

“…Instead, both the median survival and the changes in the inflammatory mediators (including HMGB-1) were similar in WT and C5L2 Ϫ/Ϫ mice. Lack of a functional role for C5L2 in ECM is consistent with observations in models of experimental placental malaria in which C5aR deficiency and antibody-mediated blockade of C5aR but not C5L2 significantly reduce fetal growth restriction and improve fetal viability (60). Collectively, these data support the view that, in the context of malaria pathogenesis, C5a appears to function predominantly through C5aR rather than C5L2.…”

Malaria Infection Alters the Expression of Hepatobiliary and Placental Drug Transporters in Pregnant Mice

“…PM is associated with increased risk of adverse outcomes for both mother and fetus, including an increased risk of anemia, preterm birth, stillbirth, and delivery of low birth weight infants. During pregnancy, malaria-infected red blood cells accumulate in the placental intervillous blood spaces, resulting in altered placental angiogenesis and vascular flow, reduced nutrient and waste transfer, placental insufficiency, and a chronic localized proinflammatory environment (Fried and Duffy, 1996;Matteelli et al, 1997;Miller et al, 2002;Conroy et al, 2013). As such, optimization of pharmacological treatment of malaria in pregnancy is a global health priority.…”

Malaria in Pregnancy: An Unrecognized Risk Factor for Neuropsychiatric Disease in Offspring?

“…Moreover in pre-clinical and clinical studies increased levels of C5a were associated with dysregulation of angiogenic factors (e.g. VEGF, endoglin, angiopoietin-1 and angiopoietin-2), placental vascular insufficiency, and an increased risk of adverse birth outcomes including LBW and stillbirth [14,15].…”

“…However, dysregulated activation or control of the complement system is associated with several adverse pregnancy outcomes, such as preeclampsia and spontaneous abortion [12,13]. Human, pre-clinical models, and in vitro studies have shown that PM is associated with increased activation of the complement system, in particular enhanced generation of the pro-inflammatory component C5a [14,15]. In vitro, C5a can induce the synergistic release of both inflammatory mediators (e.g.…”