Related Experiment Videos
P-selectin contributes to severe experimental malaria but is not required for leukocyte adhesion to brain
Wun-Ling Chang1, Jie Li, Guang Sun
1Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
Abstract:
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.
Insights
P-selectin plays a role in experimental cerebral malaria pathogenesis, as P-selectin-deficient mice show protection from death. However, P-selectin is not solely responsible for leukocyte adhesion in the brain during malaria.
Area of Science:
- Immunology
- Pathology
- Parasitology
Background:
- Experimental cerebral malaria (ECM) in Plasmodium berghei-infected mice models human malaria, showing systemic inflammation and organ damage.
- Leukocyte adhesion molecules are implicated in inflammatory responses and organ damage during malaria.
Purpose of the Study:
- To investigate the role of P-selectin in the pathogenesis of experimental cerebral malaria.
- To determine if P-selectin is essential for leukocyte adhesion in the brain during malaria.
Main Methods:
- Mice lacking P-selectin were compared to wild-type controls for survival and parasitemia.
- P-selectin levels were quantified in various organs using a dual radiolabeled monoclonal antibody technique.
- Intravital microscopy was used to visualize leukocyte rolling and adhesion in brain venules.
Main Results:
- P-selectin-deficient mice were significantly protected from death, despite similar parasite levels.
- P-selectin levels increased in multiple organs of infected mice, supporting a systemic inflammatory response.
- Significant leukocyte rolling and adhesion were observed in the brains of infected mice, peaking on day 6.
- Increased P-selectin in ECM-resistant mice suggests it's not sufficient for pathogenesis.
- Leukocyte adhesion in the brain was similar between P-selectin-deficient and control mice.
Conclusions:
- P-selectin contributes to the development of malarial pathogenesis.
- P-selectin is not required for leukocyte adhesion in the brain during experimental cerebral malaria.