The Role of Animal Models for Research on Severe Malaria

Craig, Alister G.; Grau, Georges E.; Janse, Chris J.; Kazura, James W.; Milner, Dan; Barnwell, John W.; Turner, Gareth D. H.; Langhorne, Jean

doi:10.1371/journal.ppat.1002401

Cited by 279 publications

(287 citation statements)

References 85 publications

(80 reference statements)

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“…This study proposes a potential mechanism common to the human disease. This is an important discovery for a field that has been debating the similarities and differences between ECM and HCM pathogenesis (49). Importantly, the etiology of human brain swelling and edema is currently unknown.…”

Section: Discussionmentioning

confidence: 93%

Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria

et al. 2017

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Human cerebral malaria (HCM) is a serious complication of Plasmodium falciparum infection. The most severe outcomes for patients include coma, permanent neurological deficits, and death. Recently, a large-scale magnetic resonance imaging (MRI) study in humans identified brain swelling as the most prominent predictor of fatal HCM. Therefore, in this study, we sought to define the mechanism controlling brain edema through the use of the murine experimental cerebral malaria (ECM) model. Specifically, we investigated the ability of CD8 T cells to initiate brain edema during ECM. We determined that areas of blood-brain barrier (BBB) permeability colocalized with a reduction of the cerebral endothelial cell tight-junction proteins claudin-5 and occludin. Furthermore, through small-animal MRI, we analyzed edema and vascular leakage. Using gadolinium-enhanced T1-weighted MRI, we determined that vascular permeability is not homogeneous but rather confined to specific regions of the brain. Our findings show that BBB permeability was localized within the brainstem, olfactory bulb, and lateral ventricle. Concurrently with the initiation of vascular permeability, T2-weighted MRI revealed edema and brain swelling. Importantly, ablation of the cytolytic effector molecule perforin fully protected against vascular permeability and edema. Furthermore, perforin production specifically by CD8 T cells was required to cause fatal edema during ECM. We propose that CD8 T cells initiate BBB breakdown through perforin-mediated disruption of tight junctions. In turn, leakage from the vasculature into the parenchyma causes brain swelling and edema. This results in a breakdown of homeostatic maintenance that likely contributes to ECM pathology. Approximately 70% of fatal malaria cases occur in children less than 5 years old (1). While uncomplicated Plasmodium falciparum infection is highly treatable, the most severe complication, cerebral malaria, presents a significant problem for patients. Human cerebral malaria (HCM) is characterized by disruption of the blood-brain barrier (BBB), coma, seizures, and death (2, 3). Patients that survive HCM are prone to persisting cognitive and neurological deficits after they have recovered from the infection (4, 5). While antimalarial drugs have shown efficacy in killing parasites, treatments to improve the outcome of HCM are lacking (6). Furthermore, the cellular mechanisms regulating

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Section: Discussionmentioning

confidence: 93%

Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria

et al. 2017

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“…In fact, like P. falciparum-infected RBCs, P. berghei ANKA-infected cells adhere to the host receptor molecule CD36 (18). Although there are differing views as to the degree to which parasite sequestration in humans and mice is comparable (47), no assumption in our modeling or experimental work depends on the specific mechanical properties of binding. The important assumption made is that parasites are able to leave circulation in the blood of the host through some mechanism of binding and so avoid host defense mechanisms such as the spleen and liver.…”

Section: Discussionmentioning

confidence: 98%

Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and In Vivo Models of Malaria

et al. 2014

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Parasite biomass and microvasculature obstruction are strongly associated with disease severity and death in Plasmodium falciparum-infected humans. This is related to sequestration of mature, blood-stage parasites (schizonts) in peripheral tissue. The prevailing view is that schizont sequestration leads to an increase in pathogen biomass, yet direct experimental data to support this are lacking. Here, we first studied parasite population dynamics in inbred wild-type (WT) mice infected with the rodent species of malaria, Plasmodium berghei ANKA. As is commonly reported, these mice became moribund due to large numbers of parasites in multiple tissues. We then studied infection dynamics in a genetically targeted line of mice, which displayed minimal tissue accumulation of parasites. We constructed a mathematical model of parasite biomass dynamics, incorporating schizontspecific host clearance, both with and without schizont sequestration. Combined use of mathematical and in vivo modeling indicated, first, that the slowing of parasite growth in the genetically targeted mice can be attributed to specific clearance of schizonts from the circulation and, second, that persistent parasite growth in WT mice can be explained solely as a result of schizont sequestration. Our work provides evidence that schizont sequestration could be a major biological process driving rapid, early increases in parasite biomass during blood-stage Plasmodium infection. Malaria caused approximately 1,238,000 deaths worldwide in 2010 (1). Of the five different Plasmodium species that infect humans, Plasmodium falciparum is associated with greatest morbidity (2, 3). Parasite biomass and microvasculature obstruction are among the most reliable prognostic indicators in P. falciparum-infected humans, with high levels of either indicator being strongly associated with severe disease and negative outcome (4-6). High P. falciparum biomass could in theory result from poor clearance of freely circulating parasites by the host's mononuclear phagocytic system (MPS), principally macrophages in the spleen and liver. Clinical studies, including ex vivo perfusion of human spleens and analyses of splenectomized malaria patients, argue that humans can clear at least a proportion of circulating P. falciparum parasites (7-11). Furthermore, increased rigidity of red blood cells (RBCs) infected with P. falciparum parasites, particularly mature-stage trophozoites and schizonts, appears to render them less capable of passage through the spleen than either uninfected RBCs or ring-stage P. falciparum-infected RBCs (P. falciparum-iRBCs) (12). Thus, the human MPS can clear circulating mature P. falciparum-iRBCs, but its competency at doing so in vivo remains unclear. A mechanism that could facilitate increases in parasite biomass is evasion of the host MPS by sequestration of P. falciparum-iRBCs in peripheral tissues. A large body of literature has clearly identified P. falciparum-expressed ligands, which mediate adherence of schizont-and late-stage trophozoite-iRBCs to ...

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“…These findings suggest that lethal parasites might remain viable and/or replicate in the placenta during pregnancy, and pregnant IMϩNK mice subsequently show high levels of parasitemia and placental pathology. P. falciparum adhesion to chondroitin sulfate A (CSA) and hyaluronic acid (HA) is associated with accumulation of pRBCs in placenta and is a key feature related to pathology (32,33). Protection from placental malaria in women may be mediated by antibodies to the VAR2CSA protein belonging to the clon- ally variant PfEMP1 protein family (34).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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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...

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The Role of Animal Models for Research on Severe Malaria

Cited by 279 publications

References 85 publications

Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria

Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria

Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and In Vivo Models of Malaria

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

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