Plasmodium coatneyi in the rhesus monkey (Macaca mulatta) as a model of malaria in pregnancy.

Abstract

Abstract. Pregnant women with Plasmodium falciparum infection are at increased risk for complications such as anemia and cerebral malaria. In addition, the infants of these women suffer intrauterine growth retardation (IUGR), low birth weight (LBW), congenital infection, and high infant mortality. Although much has been learned from studies of malaria during human pregnancy, progress has been limited by the lack of a suitable animal model. Nonhuman primates are of particular interest because, other than the armadillo, they are the only animals with a discoidal, villous, hemochorial placenta like that of humans. We have established a model of malaria during human pregnancy by inoculating pregnant rhesus monkeys (Macaca mulatta) with Plasmodium coatneyi (a sequestering parasite) during the first trimester. In our initial experiment, four monkeys were inoculated with a fresh inoculum containing 10 8 viable parasites from an infected donor monkey. All four monkeys became parasitemic seven days postinoculation (PI) and three monkeys aborted 7-10 days PI coincident with high peak parasitemias (41,088-374,325 parasites/mm 3 ). Although abortion is one of the outcomes observed in Plasmodium-infected women, the intent of this study was to examine the effects of Plasmodium infection throughout gestation. Since the rapid onset of high parasitemia may have been responsible for the abortions, a decision was made to reduce the size of the effective inoculum. Six additional pregnant monkeys were inoculated with a frozen isolate taken from the same donor containing 10 6 parasites. These six animals became parasitemic by 14 days PI and, along with monkey E412, carried their infants to term. These seven infants weighed significantly less at term than the infants of uninfected mothers (P ϭ 0.0355). Symmetrical IUGR was detected by ultrasound in one fetus with an LBW of 334 g. Another LBW infant (300 g) had asymmetrical growth retardation, which has been associated with uteroplacental insufficiency and was consistent with the lower placental weights found in infected dams compared with controls (P ϭ 0.0455). The infant with symmetric IUGR died at five days of age, while the other is alive but congenitally infected. The IUGR, LBW, congenital infection, postnatal infant mortality, and early abortions observed in these animals suggest that P. coatneyi in pregnant rhesus monkeys is a valid model of malaria in human pregnancy. This model should provide the opportunity to study questions about malaria in pregnancy that have been difficult to study in humans.Pregnant women are more likely to develop symptomatic malaria than their nonpregnant counterparts.

Murine Malaria Infection Induces Fetal Loss Associated with Accumulation ofPlasmodium chabaudiAS-Infected Erythrocytes in the Placenta

“…Most failed to carry their fetuses beyond mid-gestation, with higher rates of fetal resorption and abortion compared to UP mice, and none delivered live, term pups. Spontaneous abortions during the first trimester have been reported in P. coatneyi-infected, nonimmune, pregnant rhesus monkeys (16) and in P. falciparum-infected, nonimmune pregnant women (42,47,58,79). However, the immunologic mechanisms that lead to fetal loss during such nonimmune malarial infections remain to be fully elucidated.…”

“…Some progress toward this end has been made using nonimmune, pregnant rhesus monkeys infected with Plasmodium coatneyi (16). In this model, infected monkeys experienced increased rates of abortion and intrauterine growth retardation associated with placental pathology (15,16). Also, the leukocyte profiles were altered in infected pregnant monkeys, with lower CD4 ϩ and CD8 ϩ T-cell and B-cell counts that were suggestive of pregnancy-associated immunomodulation (17).…”

“…No detailed study has been done, however, to investigate antimalarial immune responses during early pregnancy in the absence of preexisting immunity or the effect of these responses on fetal outcome. Some progress toward this end has been made using nonimmune, pregnant rhesus monkeys infected with Plasmodium coatneyi (16). In this model, infected monkeys experienced increased rates of abortion and intrauterine growth retardation associated with placental pathology (15,16).…”

A Review of Plasmodium coatneyi–Macaque Models of Severe Malaria

“…32 There have been a variety of studies examining the suitability of P. coatneyi in macaques as a model for the cerebral or severe malaria caused in humans by P. falciparum, as well as for the evaluation of plasmodium-induced placental pathology. 20,21 Some of these experiments attempted to describe the pathophysiology of disease through histopathology, immunohistochemistry, and transmission electron microscopy, { while others adopted the animal model as a route of drug assessment and testing. 58,69 Figures 2-5.…”

Plasmodium coatneyi: observations on periodicity, mosquito infection, and transmission to Macaca mulatta monkeys.

“…49 Over many years, we have tried to define the biology of infections of P. coatneyi in M. mulatta, their infectivity to different mosquitoes, the development of exoerythrocytic stages, and the suitability of this model for basic immunologic and physiologic study.…”