Brain Capillary Blockage Produced by a Virulent Strain of Rodent Malaria

Yoeli, Meir; Hargreaves, Bruce J.

doi:10.1126/science.184.4136.572

Cited by 54 publications

(32 citation statements)

References 10 publications

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“…Further indirect evidence in support of the birthrate hypotheses comes from field data on severe disease: these are the positive link in P. falciparum between severe malaria and parasite multiplication potential measured in vitro (Chotivanich et al 2000), and the correlation between cytoadherence in vitro and the incidence of severe anaemia and therefore perhaps asexual multiplication rate. Laboratory studies that also support the birth-rate argument are the higher growth rate and higher sequestration in a highly virulent mutant clone of P. yoelii compared with avirulent clones (Yoeli & Hargreaves 1974;Yoeli et al 1975), and the lower acute phase growth rate and virulence in a line of P. falciparum that had lost the ability to sequester (Langreth & Peterson 1985). However, in another study of a non-sequestering line in P. chabaudi, the rate of acute phase growth was similar to that of sequestering lines (Gilks et al 1990).…”

Section: Molecular Mechanisms For Virulence In Relation To Parasite Fmentioning

confidence: 96%

“…Lesions (Vuong et al 1999) and parasites (Mota et al 2000) have been found in the brain of P. chabaudi-infected mice, but most sequestration takes place in other vital organs such as the liver (Cox et al 1987;Mota et al 2000). Brain involvement similar to cerebral malaria does occur in related rodent species (P. berghei, Rest (1982) which also sequesters in other organs (Alger 1963), and in P. yoelii, Yoeli & Hargreaves 1974;Kaul et al 1994), but this appears to be only after adaptation to the novel host (mice) through serial passage. In addition to its similarities with P. falciparum, the P. chabaudi system is attractive as a model because of the availability of diverse parasite strains cryopreserved shortly after they were derived from the wild (Beale et al 1978), the availability of host genotypes with well-characterized genetics, the ability to measure virulence, multiplication rate, gametocyte production, transmission to mosquitoes, cytoadherence and antigenic variation in vivo, and the ability to manipulate immunity and other factors that moderate virulence.…”

Section: Plasmodium Chabaudi As a Model For Virulence Evolutionmentioning

confidence: 99%

“…There are two forms of evidence in relation to the importance of selectivity in invasion rates: one in species with very high red cell selectivity, and the other in species with low selectivity. In P. yoelii, which has a strong predilection for reticulocytes, a mutation that allows parasites to also infect mature red cells leads to very rapid multiplication rate and hypervirulence (Yoeli & Hargreaves 1974;Yoeli et al 1975). This has been linked to invasion proteins located in the apex of the merozoite (Freeman et al 1980;Holder & Freeman 1981;Ogun & Holder 1996;Preiser & Jarra 1998).…”

Section: (B) Antigenic Variationmentioning

confidence: 99%

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Virulence in malaria: an evolutionary viewpoint

Mackinnon

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2004

Phil. Trans. R. Soc. Lond. B

228

205

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Malaria parasites cause much morbidity and mortality to their human hosts. From our evolutionary perspective, this is because virulence is positively associated with parasite transmission rate. Natural selection therefore drives virulence upwards, but only to the point where the cost to transmission caused by host death begins to outweigh the transmission benefits. In this review, we summarize data from the laboratory rodent malaria model, Plasmodium chabaudi, and field data on the human malaria parasite, P. falciparum, in relation to this virulence trade-off hypothesis. The data from both species show strong positive correlations between asexual multiplication, transmission rate, infection length, morbidity and mortality, and therefore support the underlying assumptions of the hypothesis. Moreover, the P. falciparum data show that expected total lifetime transmission of the parasite is maximized in young children in whom the fitness cost of host mortality balances the fitness benefits of higher transmission rates and slower clearance rates, thus exhibiting the hypothesized virulence trade-off. This evolutionary explanation of virulence appears to accord well with the clinical and molecular explanations of pathogenesis that involve cytoadherence, red cell invasion and immune evasion, although direct evidence of the fitness advantages of these mechanisms is scarce. One implication of this evolutionary view of virulence is that parasite populations are expected to evolve new levels of virulence in response to medical interventions such as vaccines and drugs.

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Section: Molecular Mechanisms For Virulence In Relation To Parasite Fmentioning

confidence: 96%

Section: Plasmodium Chabaudi As a Model For Virulence Evolutionmentioning

confidence: 99%

Section: (B) Antigenic Variationmentioning

confidence: 99%

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Virulence in malaria: an evolutionary viewpoint

Mackinnon

Read

2004

Phil. Trans. R. Soc. Lond. B

228

205

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“…Studies of VSA-specific immunity to P. falciparum malaria have been frustrated by the lack of convenient and relevant animal models. Although rodent malaria parasites lack var gene orthologs, antigenic variation and IE sequestration occur with several Plasmodium species (1,19,23,41), and these species possess multigene families that appear to encode IE surface-expressed VSA (6,16). This fact notwithstanding, only limited information regarding the roles of the products of these gene families in pathogenesis and immunity is available (21,22).…”

mentioning

confidence: 99%

Variant-Specific Immunity to Plasmodium berghei in Pregnant Mice

2009

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We have investigated the immunological basis of pregnancy-related Plasmodium berghei recrudescence in immune mice with substantial preexisting immunity. Specifically, we examined the relevance of this experimental model to the study of pregnancy-associated malaria (PAM) caused by P. falciparum in women with substantial preexisting protective immunity. We used mice with immunity induced prior to pregnancy and employed flow cytometry to assess their levels of immunoglobulin G (IgG) recognizing antigens on the surfaces of infected erythrocytes (IEs) in plasma. After immunization, the mice did not possess IgG specific for antigens on IEs obtained during pregnancy-related recrudescence but they acquired recrudescence-specific IgG over the course of several pregnancies and recrudescences. In contrast, levels of antibodies recognizing IEs from nonpregnant mice did not increase with increasing parity. Furthermore, maternal hemoglobin levels increased and pregnancy-related parasitemia decreased with increasing parity. Finally, parasitemic mice produced smaller litters and pups with lower weights than nonparasitemic mice. Taken together, these observations suggest that levels of antibodies specific for recrudescence-type IEs are related to the protection of pregnant mice from maternal anemia, low birth weight, and decreased litter size. We conclude that the model replicates many of the key parasitological and immunological features of PAM, although the P. berghei genome does not encode proteins homologous to the P. falciparum erythrocyte membrane protein 1 adhesins, which are of key importance in P. falciparum malaria. The study of P. berghei malaria in pregnant, immune mice can be used to gain significant new insights regarding malaria pathogenesis and immunity in general and regarding PAM in particular.

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“…For this reason, we have focused our attention on the model of cerebral malaria induced by P. yoelii 17XL, initially described by Yoeli and Hargreaves. 10 This lethal strain of P. yoelii arose as a spontaneous mutation from the nonlethal strain P. yoelii 17XNL. We confirmed the plugging of capillaries with parasitized erythrocytes in the brains of mice infected with P. yoelii 17XL that occurred without significant inflammation.…”

mentioning

confidence: 99%

Correlation of increased expression of intercellular adhesion molecule-1, but not high levels of tumor necrosis factor-alpha, with lethality of Plasmodium yoelii 17XL, a rodent model of cerebral malaria.

Shear¹,

Marino²,

Wanidworanun³

et al. 1998

The American Journal of Tropical Medicine and Hygiene

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Abstract. Previous studies demonstrated that Plasmodium yoelii 17XL, a lethal strain of rodent malaria, causes a syndrome in SW mice that resembles human cerebral malaria. The mouse brain pathology is characterized by cytoadherence of parasitized erythrocytes. Here, the possible mechanisms mediating cerebral malaria in this model were studied and the results were compared with a nonlethal strain of this parasite, P. yoelii 17XNL (nonlethal), which does not cause cerebral malaria. Immunostaining for intercellular adhesion molecule-1 (ICAM-1) revealed an increase in expression of this protein in the small venules and capillaries of the brains of infected mice that increased with time after infection. Staining was more pronounced during the lethal infection than the nonlethal infection. Some staining with monoclonal antibody to vascular cell adhesion molecule-1 was also observed, but it was quantitatively less than ICAM-1 staining and was limited to larger venules. During the lethal infection, levels of tumor necrosis factor-␣ (TNF-␣) increased rapidly, peaking on day 4. In contrast, mice infected with nonlethal P. yoelii had a slower serum TNF-␣ response that peaked on day 10, prior to the maximum parasitemia. In addition, mice with a targeted disruption of the TNF-␣ gene (TNF-␣Ϫ/Ϫ mice) were infected with the lethal and nonlethal strains of P. yoelii 17X. The TNF-␣Ϫ/Ϫ mice infected with the nonlethal parasite had significantly higher levels of parasitemia than controls, whereas TNF-␣Ϫ/Ϫ mice infected with the lethal strain had slightly higher levels of infected erythrocytes but were equally susceptible to death from this infection. Thus, TNF-␣ does not appear to be essential in mediating death. These results demonstrate that P. yoelii 17XL infection has features in common with human cerebral malaria and suggest that this model may be useful in testing strategies to alleviate this syndrome.Cerebral malaria refers to the severe complications of falciparum malaria in which vascular plugging of Plasmodium falciparum-infected red blood cells (RBCs) in the brain can lead to coma and death, often in children. 1,2 Cytoadherence of parasitized RBCs to endothelial cells, via ligands present on the erythrocyte membrane knobs, is thought to be responsible for this phenomenon. 3 However, exceptions to the requirement for knobs have been observed. 4 Others have postulated an important role for cytokines and nitric oxide in the pathogenesis of cerebral malaria. 5 The molecular mechanisms underlying the cytoadherence of P. falciparum-infected RBCs to the endothelium is under intensive investigation. Most laboratory-maintained and field isolates of infected RBCs appear to bind to CD36. However, binding to intercellular adhesion molecule-1 (ICAM-1) has also been observed. 4 Importantly, variation in specificity for endothelial ligands is common among different isolates. 6 Vascular cell adhesion molecule-1 (VCAM-1), a member of the same immunoglobulin-like superfamily as ICAM-1, and E-selectin have also been found to be receptors f...

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Brain Capillary Blockage Produced by a Virulent Strain of Rodent Malaria

Cited by 54 publications

References 10 publications

Virulence in malaria: an evolutionary viewpoint

Virulence in malaria: an evolutionary viewpoint

Variant-Specific Immunity to Plasmodium berghei in Pregnant Mice

Correlation of increased expression of intercellular adhesion molecule-1, but not high levels of tumor necrosis factor-alpha, with lethality of Plasmodium yoelii 17XL, a rodent model of cerebral malaria.

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