Microvascular hemodynamics and in vivo evidence for the role of intercellular adhesion molecule-1 in the sequestration of infected red blood cells in a mouse model of lethal malaria.

Kaul, Dhananjay K.; Liu, Xiao-du; Nagel, Ronald L.; Shear, Hannah L.

doi:10.4269/ajtmh.1998.58.240

Cited by 40 publications

(26 citation statements)

References 52 publications

(61 reference statements)

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“…Our data do not support the assertion that elevated vcam-1 corresponds to ECM, as we observed slightly higher vcam-1 mRNA levels in ⌬hmgb2 ANKA-infected mice at d6 postinfection than in WT P. berghei ANKA-infected C57BL/6 mice, suggesting an uncertain or perhaps protective role for this adhesion molecule in our model. In concordance with our observation of a predominant role for ICAM-1 compared to VCAM-1 in malaria pathogenesis, infusion of an anti-ICAM-1 but not an anti-VCAM-1 monoclonal antibody prevented cytoadherence of infected erythrocytes in a P. yoelii model of ECM (65), in addition to in vivo evidence for the role of ICAM-1 in the sequestration of infected red blood cells in a mouse model of lethal malaria (66). In contrast, the transcript level of the cytoprotective heme oxygenase gene (hmox-1) was markedly increased at d6 in ⌬hmgb2 ANKAinfected C57BL/6 mice and was thus consistent with the literature (9-11).…”

Section: Discussionsupporting

confidence: 67%

Disruption of Parasitehmgb2Gene Attenuates Plasmodium berghei ANKA Pathogenicity

et al. 2015

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h Eukaryotic high-mobility-group-box (HMGB) proteins are nuclear factors involved in chromatin remodeling and transcription regulation. When released into the extracellular milieu, HMGB1 acts as a proinflammatory cytokine that plays a central role in the pathogenesis of several immune-mediated inflammatory diseases. We found that the Plasmodium genome encodes two genuine HMGB factors, Plasmodium HMGB1 and HMGB2, that encompass, like their human counterparts, a proinflammatory domain. Given that these proteins are released from parasitized red blood cells, we then hypothesized that Plasmodium HMGB might contribute to the pathogenesis of experimental cerebral malaria (ECM), a lethal neuroinflammatory syndrome that develops in C57BL/6 (susceptible) mice infected with Plasmodium berghei ANKA and that in many aspects resembles human cerebral malaria elicited by P. falciparum infection. The pathogenesis of experimental cerebral malaria was suppressed in C57BL/6 mice infected with P. berghei ANKA lacking the hmgb2 gene (⌬hmgb2 ANKA), an effect associated with a reduction of histological brain lesions and with lower expression levels of several proinflammatory genes. The incidence of ECM in pbhmgb2-deficient mice was restored by the administration of recombinant PbHMGB2. Protection from experimental cerebral malaria in ⌬hmgb2 ANKA-infected mice was associated with reduced sequestration in the brain of CD4؉ and CD8 ؉ T cells, including CD8 ؉ granzyme B ؉ and CD8 ؉ IFN-␥ ؉ cells, and, to some extent, neutrophils. This was consistent with a reduced parasite sequestration in the brain, lungs, and spleen, though to a lesser extent than in wild-type P. berghei ANKA-infected mice. In summary, Plasmodium HMGB2 acts as an alarmin that contributes to the pathogenesis of cerebral malaria.

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Section: Discussionsupporting

confidence: 67%

Disruption of Parasitehmgb2Gene Attenuates Plasmodium berghei ANKA Pathogenicity

et al. 2015

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“…Upregulation of mediators of pathology during CM has been reported previously in both murine (19) and human (33) malaria. Hence, it was important to document these phenomena in this model.…”

Section: Resultsmentioning

confidence: 96%

Immunopathology of Cerebral Malaria: Morphological Evidence of Parasite Sequestration in Murine Brain Microvasculature

Hearn

Rayment

Landon³

et al. 2000

Infect Immun

151

126

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A murine model that closely resembles human cerebral malaria is presented, in which characteristic features of parasite sequestration and inflammation in the brain are clearly demonstrable. "Young" (BALB/c ؋ C57BL/6)F 1 mice infected with Plasmodium berghei (ANKA) developed typical neurological symptoms 7 to 8 days later and then died, although their parasitemias were below 20%. Older animals were less susceptible. Immunohistopathology and ultrastructure demonstrated that neurological symptoms were associated with sequestration of both parasitized erythrocytes and leukocytes and with clogging and rupture of vessels in both cerebral and cerebellar regions. Increases in tumor necrosis factor alpha and CD54 expression were also present. Similar phenomena were absent or substantially reduced in older infected but asymptomatic animals. These findings suggest that this murine model is suitable both for determining precise pathogenetic features of the cerebral form of the disease and for evaluating circumventive interventions.Human cerebral malaria (CM) is a serious neurological condition that can lead to coma and death. Its principal feature is endothelial damage associated with the sequestration of Plasmodium falciparum schizonts within the microvasculature of the brain (24). However, studying CM in humans is difficult because of the inability to correlate pathological changes precisely with the clinical features. This is an important prerequisite in the treatment of CM. Therefore, there is an obvious need for experimental models that bear close similarity to human CM in order to understand the precise mechanisms leading to coma and death and for the development of therapeutic regimens. The phenomenon has been extensively studied in experimental animals in order to find a system that closely resembles CM in humans. Primate models, particularly that of Plasmodium coatneyi infections in rhesus monkeys (21), have given encouraging results but are limited by practical and financial constraints. Murine models are more suitable for experimental studies, but thus far it has always been suggested that the findings do not resemble those seen during human CM exactly. In both human and mouse, tumor necrosis factor alpha (TNF)-induced upregulation of endothelial adhesion molecules has been invoked as a factor in pathology involving the sequestration of cells within the microvasculature of the brain and other major organs of the body (15, 16). However, other studies have suggested that there are differences between the two species, with a preference for leukocyte sequestration in the mouse (14) rather than for parasitized red blood cell sequestration, as seen in humans (1).In our previous studies on the role of cytokines during various blood-stage malaria infections (12), we observed that Plasmodium berghei ANKA infections in "young" 8-week-old (BALB/c ϫ C57BL/6)F 1 mice frequently resulted in neurological symptoms and early death (de Souza et al., unpublished observations). These characteristic CM-associated symptoms were less c...

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“…19 Importantly, in our recent studies, we have found that anti-ICAM MAb can reverse cytoadherence in vivo and release schizonts into the circulation. 20 Thus, ICAM-1, and not VCAM-1, is a likely cytoadherence molecule in this model.…”

Section: Discussionmentioning

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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Microvascular hemodynamics and in vivo evidence for the role of intercellular adhesion molecule-1 in the sequestration of infected red blood cells in a mouse model of lethal malaria.

Cited by 40 publications

References 52 publications

Disruption of Parasitehmgb2Gene Attenuates Plasmodium berghei ANKA Pathogenicity

Disruption of Parasitehmgb2Gene Attenuates Plasmodium berghei ANKA Pathogenicity

Immunopathology of Cerebral Malaria: Morphological Evidence of Parasite Sequestration in Murine Brain Microvasculature

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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