ICAM-1 is a key receptor mediating cytoadherence and pathology in the Plasmodium chabaudi malaria model

Abstract

BackgroundParasite cytoadherence within the microvasculature of tissues and organs of infected individuals is implicated in the pathogenesis of several malaria syndromes. Multiple host receptors may mediate sequestration. The identity of the host receptor(s), or the parasite ligand(s) responsible for sequestration of Plasmodium species other than Plasmodium falciparum is largely unknown. The rodent malaria parasites may be useful to model interactions of parasite species, which lack the var genes with their respective hosts, as other multigene families are shared between the species. The role of the endothelial receptors ICAM-1 and CD36 in cytoadherence and in the development of pathology was investigated in a Plasmodium chabaudi infection in C57BL/6 mice lacking these receptors. The schizont membrane-associated cytoadherence (SMAC) protein of Plasmodium berghei has been shown to exhibit reduced CD36-associated cytoadherence in P. berghei ANKA-infected mice.MethodsParasite tissue sequestration and the development of acute stage pathology in P. chabaudi infections of mice lacking CD36 or ICAM-1, their respective wild type controls, and in infections with mutant P. chabaudi parasites lacking the smac gene were compared. Peripheral blood parasitaemia, red blood cell numbers and weight change were monitored throughout the courses of infection. Imaging of bioluminescent parasites in isolated tissues (spleen, lungs, liver, kidney and gut) was used to measure tissue parasite load.ResultsThis study shows that neither the lack of CD36 nor the deletion of the smac gene from P. chabaudi significantly impacted on acute-stage pathology or parasite sequestration. By contrast, in the absence of ICAM-1, infected animals experience less anaemia and weight loss, reduced parasite accumulation in both spleen and liver and higher peripheral blood parasitaemia during acute stage malaria. The reduction in parasite tissue sequestration in infections of ICAM-1 null mice is maintained after mosquito transmission.ConclusionsThese results indicate that ICAM-1-mediated cytoadherence is important in the P. chabaudi model of malaria and suggest that for rodent malarias, as for P. falciparum, there may be multiple host and parasite molecules involved in sequestration.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1834-8) contains supplementary material, which is available to authorized users.

Elimination of intravascular thrombi prevents early mortality and reduces gliosis in hyper-inflammatory experimental cerebral malaria

“…However, because of the overlap of inflammation with parasite-dependent factors, determining the independent contributions of each presents an ongoing challenge to investigators. The impact of parasite adhesion to the vascular endothelium on coagulation, vascular integrity, and congestion has been shown in in vitro endothelial cultures and animal models of cerebral malaria [ 19 , 43 , 67 , 84 , 85 ]. Sequestration is seen in most fatal pediatric and adult CM cases [ 20 , 21 ] and is used as a critical hallmark of disease.…”

“…The P. chabaudi life cycle is synchronous. Mature schizonts disappear from the circulation almost completely and are found sequestered primarily in the liver and lungs of mice in a partially ICAM1-dependent manner [ 19 ]. Interestingly, pathological damage within each organ in P. chabaudi does not correspond to the degree of organ-specific sequestration of the parasite [ 18 ].…”

Neutrophil extracellular traps drive inflammatory pathogenesis in malaria

“…The difference in abundance of neutrophils in livers of WT and knockout animals was greater than the difference observed in peripheral blood, indicating that, in addition to emergency granulopoiesis, NETs regulate neutrophil trafficking. Interestingly, both neutrophils [53] and parasites [54,55] can use the same receptor to dock to endothelial cells: intercellular adhesion molecule 1 (ICAM-1). We hypothesized that NET components regulate expression of ICAM-1 on the endothelium.…”

“…Whether NETs can also upregulate ICAM-1 on human brain endothelium remains to be verified.NET components are also required for pathology and parasite sequestration in the lungs of infected animals, demonstrating that this mechanism may be broadly generalizable to different vascular beds. Furthermore, in the P. chabaudi model, lung sequestration is mediated by an unidentified receptor other than ICAM-1[54], alarmins can induce the maturation and activation of dendritic cells, T cells, macrophages and endothelial cells[75]. Additional experiments will determine which NET-bound proteins are responsible for triggering granulopoiesis and endothelial activation.NET-associated molecules are necessary but not sufficient to drive inflammation in P. chabaudi malaria, as shown by the injection of NET fragments into uninfected mice.…”

When Epidemiology Is the Clue to a Positive Outcome: A Case of Malaria During Pregnancy

“…The pathophysiology of the placental infection in cases of P. falciparum occurs by the accumulation of the infected erythrocytes that express the VAR2CSA protein that adheres to the chondroitin sulfate proteoglycans (primarily), hyaluronic acid, and other receptors present in the syncytiotrophoblast, causing ischemia of the placental tissue [ 7 , 8 ]. P. vivax has not been confirmed to sequester in the placenta, but it has been proposed that involvement of ICAM-1 and CSA, as key receptors, mediate cytoadherence and pathology [ 9 , 10 ].…”