Susceptibility to Experimental Cerebral Malaria Induced byPlasmodium bergheiANKA in Inbred Mouse Strains Recently Derived from Wild Stock

Abstract

The neurological syndrome caused by Plasmodium berghei ANKA in rodents partially mimics the human disease. Several rodent models of cerebral malaria (CM) exist for the study of the mechanisms that cause the disease. However, since common laboratory mouse strains have limited gene pools, the role of their phenotypic variations causing CM is restricted. This constitutes an obstacle for efficient genetic analysis relating to the pathogenesis of malaria. Most common laboratory mouse strains are susceptible to CM, and the same major histocompatibility complex (MHC) haplotype may exhibit different levels of susceptibility. We analyzed the influence of the MHC haplotype on overcoming CM by using MHC congenic mice with C57BL/10 and C3H backgrounds. No correlation was found between MHC molecules and the development of CM. New wild-derived mouse strains with wide genetic polymorphisms were then used to find new models of resistance to CM. Six of the twelve strains tested were resistant to CM. For two of them, F 1 progeny and backcrosses performed with the reference strain C57BL/6 showed a high level of heterogeneity in the number and characteristics of the genetic factors associated with resistance to CM.Cerebral malaria (CM) is an immunophysiopathological process caused by Plasmodium falciparum in humans and Plasmodium berghei ANKA in rodents. CM causes over 2 million deaths per year, mainly in young children. The clinical features of CM are well documented, but many aspects of its pathogenesis remain unclear. A number of parameters influence the severity of CM, including the genotype (22), the transmission level of the parasite, and the age (2), immune status (6), and genetic factors (8,12,17) of the host. However, the exact roles that these factors play are still not understood.In the past, several attempts have been made to develop rodent models to study the mechanisms that lead to cerebral disease in patients with malaria. These include efforts in rats (19), golden hamsters (26), and mice (16, 25, 26) infected with either P. berghei ANKA or K173. P. berghei ANKA, isolated from Thicket rats (Grammomys surdaster) (30), can induce a neurological syndrome that partially mimics human CM in susceptible rodent laboratory strains. The symptoms associated with CM in current mouse models include respiratory distress syndrome, decreased body temperature, and neurological manifestations characterized by ataxia, paralysis (mono-, hemi-, and tetraplegia), and coma, followed by death (10). Even though these models do not exhibit all of the features of the human syndrome (28, 31), they were used to show that the sequestration of leukocytes (21) and parasitized erythrocytes (10) in the small vessels of the brain (24) and endothelial-cell damage (20,29) are involved in pathogenesis. The histopathological changes involved in both human and murine CM are characterized by loss of vascular cell integrity, tissue edema, and congestion of microvessels with parasitized erythrocytes and/or mononuclear cells (18). Sequestration has been attrib...

Common Strategies To Prevent and Modulate Experimental Cerebral Malaria in Mouse Strains with Different Susceptibilities

“…All of these cytokines, except IL-10, play negative roles in disease outcome. Interestingly, susceptibility/resistance loci have been mapped to different chromosomes within the genome of CBA and B6 mice (4,32,34), indicating that factors critical to ECM development may be different between the two strains of mice (34). This is consistent with human CM, which is considered to be a syndrome with significant heterogeneity in disease development and manifestation between affected individuals (11,27).…”

Genetic control of parasite clearance leads to resistance to Plasmodium berghei ANKA infection and confers immunity

“…[16][17][18] We have previously exploited the genetic diversity represented by these strains in order to identify phenotypes related to malaria susceptibility/ resistance and to dissect their genetic control. 12,19 Using this approach, we reported a novel phenotype constituted by survival and cure from infection by P. berghei ANKA. This phenotype was represented in 10% of (WLAxC57BL/6)F2 mice, while all the remaining individuals died either early with low parasitaemia, in some cases with clear signs of ECM (17.4%), or later due to HP (72.6%).…”

Suppression of CD4+Effector Responses by Naturally Occurring CD4+CD25+Foxp3+Regulatory T Cells Contributes to Experimental Cerebral Malaria

“…Therefore, we used CM-resistant (CMR) (WLA ϫ B6) F1 mice irradiated at 300 rads, which provide a model of P. berghei ANKA-mediated lethal hemolytic anemia associated with HP. This model provides excellent tool for analyzing the physiological pathways involved in disease processes to fatal syndromes during malaria and is totally compatible as F1 mice cannot reject the parental transferred cells (34). Donor B6 nTreg did not reverse the CMR phenotype of these mice but significantly decreased the frequency of mice that survived the HP phase, compared to those in the control and naive CD4 ϩ T cell groups (P Ͻ 0.05) (Fig.…”