Development of Severe Pathology in Immunized Pregnant Mice Challenged with Lethal Malaria Parasites

Abstract

b Pregnant women are highly susceptible to malaria infection because of their low immunity and are at increased risk of maternal illness or death, in addition to spontaneous abortion, stillbirth, premature delivery, and low birth weight. However, the detailed pathogenesis of maternal malaria remains unclear. In this study, we evaluated a mouse model that shows similar severe pathological features of pregnant women during Plasmodium falciparum infection and investigated the pathogenesis of maternal malaria. Pregnant mice immunized by infection with an attenuated parasite, Plasmodium berghei XAT, were more susceptible to virulent P. berghei NK65 challenge/infection than were nonpregnant mice and showed high levels of parasitemia and a poor pregnancy outcome associated with placental pathology, such as accumulation of parasitized red blood cells, in the late phase of pregnancy. Notably, the pregnant immune mice challenged/infected with P. berghei NK65 developed liver injury associated with microvesicular fatty infiltration in late pregnancy. The pathological features were similar to acute fatty liver of pregnancy. Higher levels of gamma interferon and nitric oxide (NO) were found in plasma from pregnant immune mice infected with P. berghei NK65 than in plasma from nonpregnant mice. These findings suggest that development of liver injury and placental pathology in pregnant immune mice challenged/infected with P. berghei NK65 is accompanied by enhanced production of proinflammatory cytokines. Malaria is the most devastating parasitic disease of humans in tropical and subtropical regions, resulting in an estimated 0.6 to 1 million deaths per year (1). The populations at greatest risk of developing severe pathology are children under the age of 5 years and pregnant women in areas where Plasmodium falciparum is endemic (2-4). Every year, approximately 50 million women living in areas where malaria is endemic become pregnant. An estimated 10,000 of these women and 200,000 of their fetuses or infants die annually as a result of malaria during pregnancy (1, 2). Malaria during pregnancy is a major public health problem in areas of endemicity, especially in Africa.People living in regions where malaria is endemic acquire protective immunity against malaria parasites and often show asymptomatic infection. However, women are highly susceptible to malaria infection because of their low immunity during pregnancy and are at increased risk of maternal illness or death (5, 6). Malaria during pregnancy, in addition to maternal illness or death, is implicated in the occurrence of spontaneous abortion, stillbirth, premature delivery, and low birth weight (6). Recently, it has been demonstrated that pregnant mice infected with lethal Plasmodium berghei parasites show a feature similar to placental pathology and subsequently poor pregnancy outcome (7,8).Cerebral malaria (CM) or respiratory distress syndrome has been reported to be an infrequent but relevant cause of maternal death in women living in an area of sub-Saharan Africa where m...

Heme oxygenase-1 is critically involved in placentation, spiral artery remodeling, and blood pressure regulation during murine pregnancy

“…In fact, plasmodium infection during gestation is related to severe clinical manifestations including abortion and stillbirth. In a mice model of severe placental malaria (after infection with Plasmodium berghei ), both mothers and fetuses often succumb to infection before or immediately after delivery ( Mineo et al, 2013 ). P. berghei -infected erythrocytes accumulate in the placenta, where they are then phagocytized by trophoblasts ( de Moraes et al, 2013 ; Lima et al, 2014 ).…”

Malaria in pregnancy: the relevance of animal models for vaccine development

“…High levels of anti-inflammatory cytokines (such as IL-10) have also been observed, though these were insufficient to prevent fetal loss 37,39 . Conversely, P berghei in non-immune pregnant mice was reported to cause increased levels of IL-17 and reduced levels of IL-10 that were associated with lower birth weights of offspring 35 , although other studies have not seen these relationships 43–45 . Increased levels of complement C5a and C5a receptor in infected mice have been associated with poor fetal growth, and mutant mice lacking the C5a receptor delivered significantly heavier offspring 46 .…”

“…Both heterologous re-infection with P. berghei NK65 during pregnancy and homologous re-infection with P. berghei K173 during pregnancy led to dysregulated inflammatory responses and significantly lower birth weight of pups 44,45 . The observations seen in re-infection models suggest that, despite previously acquired immunity, mice remain susceptible to re-infection of the same species during pregnancy, likely by parasite expression of VSA to evade preexisting immunity as observed in the recrudescent model 36 .…”

“…The absence of var genes, especially VAR2CSA, could explain why P chabaudi parasites do not sequester in the placenta, although the absence of var genes does not preclude sequestration in other vascular beds. Of note, P vivax also lacks var genes and shares several protein orthologs such as pir genes that encode a variant antigen family with P chabaudi 45 . Since P vivax MiP does not involve placental parasite sequestration 12,13 , and in vitro studies have failed to identify a P vivax adhesion phenotype related to MiP 51 , systemic infection in the mother may more likely explain poor pregnancy outcomes.…”

Malaria in the postpartum period causes damage to the mammary gland

“…The mammary gland tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections 6 μm thick were stained with hematoxylin and eosin (H&E) as previously described [ 35 – 37 ]. The stained sections were photographed at 20×, 100×, and 400× magnification using an All-in-One Fluorescence Microscope (BZ9000; KEYENCE Japan, Osaka, Japan).…”