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

Abstract

Background: Parasite 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.

Methods: Parasite 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.

Results: This 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.

Conclusions: These 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.

Keywords: CD36; ICAM-1; Plasmodium chabaudi; SMAC; Schizont membrane-associated cytoadherence protein; Sequestration.

Fig. 1

The ICAM-1 receptor and not the CD36 receptor impacts acute stage pathology of Plasmodium chabaudi AS infections. Peripheral blood parasitaemia (a, d) anaemia (b, e) and weight loss (c, f) were compared in serially blood passaged P. chabaudi AS infections of icam-1−/− mice (a–c), cd36−/− mice (d–f) and their controls. Infections in mice lacking the ICAM-1 receptor resulted in less severe weight loss (day 9, **p < 0.01) and anaemia (day 9, *p < 0.05), yet parasite levels in peripheral blood were higher at this time point (*p < 0.05), compared to infections of wt mice. Infections in cd36−/− animals showed similar anaemia, weight loss and peripheral blood parasitaemia as infections of wt animals throughout the infection (n = 6)

Fig. 2

The ICAM-1 receptor, but not the CD36 receptor, plays a role in sequestration. a A higher proportion of schizonts (Sz) were seen in peripheral blood of icam-1−/− mice at the time of schizogony (GMT 13:30, day 7 post-infection, **p < 0.01) compared to wild-type mice. Proportions of rings (R) and trophozoites (T) were similar to control wt mice. The proportion of peripheral blood schizonts seen in peripheral blood of cd36−/− mice was similar to that of control wt mice (n = 6). b Tissue parasites were reduced in spleen and liver of icam-1−/− mice, after the infection peak (day 9, *p < 0.05). At earlier time points (day 5 or 7 post-infection) no significant differences in tissue parasites were seen. Infections of cd36−/− mice showed similar sequestration patterns to those observed in wild type animals throughout the infection (n = 5)

Fig. 3

Interaction with the ICAM-1 receptor is maintained after vector transmission of the parasite. Tissue parasites were reduced in spleen (*p < 0.05) and liver (**p < 0.01) of mice infected with recently mosquito-transmitted P. chabaudi AS parasites at day 9 post-infection but not at the earlier time point (day 5) (n = 6)

Fig. 4

Acute stage pathology increases but parasite tissue sequestration is unchanged in Plasmodium chabaudi parasites lacking SMAC. a Wild-type parasites attained a higher peripheral blood parasitaemia after the peak of infection than mice infected with PcASΔsmac parasites (*p < 0.05) (n = 9). b The proportion of schizonts (SZ) appearing in the peripheral blood increased, for Δsmac mutants compared to wild-type parasites (**p < 0.01), enumerated at the time of schizogony (GMT 13:30, day 7 post-infection). Proportions of rings (R) and trophozoites (T) were similar to control wt parasites (n = 6). c The mutant parasites showed more severe weight loss around the infection peak (day 7, **p < 0.01; d9, * p < 0.05) (n = 9). d Red blood cell loss was similar to that observed in mice infected with wt parasites (n = 9). e Δsmac and wt parasites accumulated at similar levels in the liver, lungs, and gut both pre (day 4), during (day 7) and post (day 9) infection peak (n = 6)