Homeostasis Maintenance in Plasmodium-Infected Placentas: Is There a Role for Placental Autophagy During Malaria in Pregnancy?

Abstract

Malaria represents a significant public health burden to populations living in developing countries. The disease takes a relevant toll on pregnant women, who are more prone to developing severe clinical manifestations. Inflammation triggered in response to P. falciparum sequestration inside the placenta leads to physiological and structural changes in the organ, reflecting locally disrupted homeostasis. Altogether, these events have been associated with poor gestational outcomes, such as intrauterine growth restriction and premature delivery, contributing to the parturition of thousands of African children with low birth weight. Despite significant advances in the field, the molecular mechanisms that govern these outcomes are still poorly understood. Herein, we discuss the idea of how some housekeeping molecular mechanisms, such as those related to autophagy, might be intertwined with the outcomes of malaria in pregnancy. We contextualize previous findings suggesting that placental autophagy is dysregulated in P. falciparum-infected pregnant women with complementary research describing the importance of autophagy in healthy pregnancies. Since the functional role of autophagy in pregnancy outcomes is still unclear, we hypothesize that autophagy might be essential for circumventing inflammation-induced stress in the placenta, acting as a cytoprotective mechanism that attempts to ensure local homeostasis and better gestational prognosis in women with malaria in pregnancy.

Keywords: Autophagy; Inflammation; Malaria; Placenta; Plasmodium; Pregnancy.

Figure 1

Schematic representation of autophagy in mammalian cells. (A) Autophagy proceeds through a series of events that begin with phagophore formation, elongation, and maturation into an autophagosome. The autophagosome fuses with a lysosome to form the autolysosome, followed by the degradation of selected cargo. Autophagy is tightly regulated by protein complexes produced from autophagy-related genes (ATGs) and its execution relies mostly on ULK1 and Beclin1 complexes (phagophore isolation), ATG9 and VMP1 (phagophore elongation), the ATG12 complex and LC3 (phagophore maturation into autophagosomes), and Rab7 GTPase (autophagosome-lysosome fusion for autophagy completion). (B) Cells transduce distinct signals that equally induce autophagy. Starvation, growth factor and amino acid depletion induces autophagy via AMPK and AKT, which blocks the inhibitory action of mTOR over the autophagy inducers ULK1 and Beclin1. Oxidative stress and hypoxia induce autophagy via elf2α, JNK1 and HIF, being the latter responsible for disrupting the inhibitory action of Bcl2 over Beclin1. Damaged organelles such as mitochondria induce autophagy, which digests damaged organelles and prevents cells death resulting from apoptosis. Immune system activation induces autophagy via TLR signaling upon pathogen sensing by destabilizing Bcl2-Beclin1 interaction. Autophagy is also activated or inhibited by TNF-α and IL-10, respectively. Inflammasome activity also induces autophagy, which works to counteract its overactivation resulting from excessive inflammatory signals. Pathogens directly induce autophagy, besides activating the immune system, which suppresses pathogen development by directly targeting them for degradation. ROS, reactive oxygen species; TLR, Toll-like receptor.

Figure 2

The hypothetical role of placental autophagy during malaria in pregnancy. During MiP, immune system activation in response to local infection results in inflammation and placental homeostasis imbalance. Monocytes and trophoblasts recognize infected red blood cells and parasite-derived antigens (dsDNA, GPI and hemozoin) via TLRs, which promote the downstream production of cytokines such as TNF-α and IL-1β (upon being processed by the inflammasome). TLR-MyD88-TRIF signaling might trigger autophagy by disrupting the Bcl2-Beclin1 interaction or through the paracrine action of the produced cytokines. In addition, inflammation leads to the downregulation of glucose/amino acid transporters, consequently activating autophagy upon mTOR inhibition. The hypoxic environment and ROS produced by monocytes might also induce autophagy by promoting oxidative stress and mitochondrial instability. Consequent activation of apoptotic machinery might also activate autophagy. As such, a multitude of stimuli might induce placental autophagy above basal levels, which might function as a cytoprotective mechanism that maintains local homeostasis and proper gestational development when stress intensity is low. In these circumstances, autophagy might circumvent lethal outcomes that may arise from activation of cell death mechanisms. However, persisting infection and sustained inflammation might increase cellular stress by activating programmed cell death mechanisms that regulate pyroptosis and apoptosis, for instance. First, autophagy might act as a survival mechanism by promoting nutrient recycling and destroying death signals such as inflammasome machinery and damaged mitochondria. However, if stress input increases above a given threshold, cell death executors such as apoptotic caspases might degrade autophagy-related proteins, consequently impairing their cytoprotective functions. Therefore, tissue homeostasis will not be maintained, resulting in the dysregulation of placental physiology, eventually leading to MiP poor pregnancy outcomes. dsDNA, parasite double-stranded DNA; iRBC, infected red blood cells; GPI, glycosylphosphatidylinositol; ROS, reactive oxygen species; TLR – Toll-like receptor.