P-selectin contributes to severe experimental malaria but is not required for leukocyte adhesion to brain microvasculature.
Plasmodium berghei-infected mice, a well-recognized model of experimental cerebral malaria (ECM), exhibit many of the hallmarks of a systemic inflammatory response, with organ damage in brain, lung, and kidneys. Identification of the molecules mediating pathogenesis of the inflammatory response, such as leukocyte adhesion, may lead to new therapies. Indeed, mice lacking the cell adhesion molecule P-selectin were significantly (P = 0.005) protected from death due to P. berghei malaria compared with C57BL/6 controls despite similar parasitemia (P = 0.6) being found in both groups of mice. P-selectin levels assessed by the quantitative dual radiolabeled monoclonal antibody technique increased significantly (P < 0.05) in several organs in C57BL/6 mice infected with P. berghei, supporting the concept of a systemic inflammatory response mediating malarial pathogenesis. Intravital microscopic analysis of the brain microvasculature demonstrated significant (P < 0.001) leukocyte rolling and adhesion in brain venules of P. berghei-infected mice compared with those found in uninfected controls. The maximum leukocyte adhesion occurred on day 6 of P. berghei infection, when the mice become moribund and exhibit marked vascular leakage into the brain, lung, and heart. However, P-selectin levels were significantly (P < 0.005) increased in brain, lung, and kidneys during P. berghei malaria in ECM-resistant BALB/c mice compared with those found in uninfected BALB/c controls, indicating that increased P-selectin alone is not sufficient to mediate malarial pathogenesis. Leukocyte adhesion to brain microvessels of P-selectin-deficient mice with P. berghei malaria was similar to that observed in control mice. Collectively, these results indicate that P-selectin is important for the development of malarial pathogenesis but is not required for leukocyte adhesion in brain.
Chang
Wun-Ling
WL
Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
Li
Jie
J
Sun
Guang
G
Chen
Hong-Li
HL
Specian
Robert D
RD
Berney
Seth Mark
SM
Granger
D Neil
DN
van der Heyde
Henri C
HC
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000469:parasitology; D002448:Cell Adhesion; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000502:physiology*; D016779:Malaria, Cerebral / Q000469:parasitology / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D019007:P-Selectin / Q000378:metabolism*; D010962:Plasmodium berghei / Q000472:pathogenicity*
D019007:P-Selectin