Pathogenic Role of P-Selectin in Experimental Cerebral Malaria

Abstract

P-selectin is a leukocyte adhesion receptor expressed on the surface of activated platelets and endothelial cells. Its role in the pathogenesis of cerebral malaria was explored in a murine model of cerebral malaria. Infection of mice with Plasmodium berghei ANKA led to P-selectin up-regulation in brain vessels of cerebral malaria-susceptible mice but not of cerebral malaria-resistant mice. Treatment of susceptible mice with anti-mouse P-selectin mAb failed to prevent the development of the neurological syndrome. However, P-selectin-deficient mice infected with Plasmodium berghei ANKA had a cumulative incidence of cerebral malaria which was significantly reduced compared to wild-type animals (4.5% versus 80%, respectively), despite identical levels of parasitemia, platelet and leukocyte accumulation. To determine whether P-selectin on platelets and/or endothelium was responsible for the microvascular pathology, cerebral malaria was assessed in chimeric mice deficient in platelet or endothelial P-selectin, which were generated by bone marrow transplantation. Mice deficient only in endothelial P-selectin did not show any sign of cerebral malaria (vascular plugging, hemorrhages, or edema), while mice lacking only platelet P-selectin showed signs of cerebral malaria similar to that seen in wild-type mice. These results indicate that endothelial P-selectin plays an important role in the pathogenesis of cerebral malaria.

Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease

“…Leukocyte rolling in these mice was unimpaired -indicating that resistance to ECM was not due to decreased leukocyte sequestration in the brain -but pRBC sequestration within the brain was not specifically examined. Similarly, mice with specific defects in endothelial cell expression of P-selectin are also resistant to ECM but, again, pRBC sequestration was not reported (Combes et al 2004). Clearly, more detailed examinations of these mouse strains are required to determine whether ECM resistance is due to reduced pRBC sequestration, attenuation of immune responses (including suboptimal T cell activation) or both.…”

An evolutionary history of the selectin gene cluster in humans

“…SELP has been involved in the pathogenesis of severe malaria, a disease that is commonly regarded as the strongest selective pressure acting on the human genome (Pozzoli et al, 2010). P-selectin contributes to the cytoadherence of infected erythrocytes to the brain microvasculature (Rowe et al, 2009) and mice that specifically lack endothelial expression of Selp are protected against cerebral malaria (Combes et al, 2004). The parasite ligand for P-selectin is thought to be represented by PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1), as the two proteins bind in vitro (Senczuk et al, 2001).…”

Potential Efficacy of Citicoline as Adjunct Therapy in Treatment of Cerebral Malaria

“…The tissue was prepared for thin paraffin sectioning. The hematoxylin-eosin-stained sections analyzed had no histopathological features associated with CM to widespread hemorrhage, a high degree of edema and leukocyte and parasitized red blood cell adherence to the endothelium throughout the brain, plugging of microvessels, and some necrosis of microvessels (30). In this study, histopathology was mainly used to confirm CM.…”