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Comparisons between microvascular changes in cerebral and non-cerebral malaria in mice, using the retinal whole-mount
A L Neill1, T Chan-Ling, N H Hunt
1Department of Pathology, University of Sydney, N.S.W., Australia.
Abstract:
CBA/T6 mice inoculated with Plasmodium berghei ANKA strain (PbA) exhibited cerebral symptoms and died from cerebral malaria 6-8 days p.i. whereas DBA/2J mice developed (around days 6-9) a non-fatal cerebral malaria, with milder cerebral symptoms, and died between days 15 and 22 from other malaria-related complications. When inoculated with P. berghei K173 (Pb) these mouse strains did not develop cerebral malaria. These mouse/parasite strain combinations were used, in conjunction with the retinal whole-mount technique, to elucidate factors critical in the pathology of murine cerebral malaria. CBA/T6 mice infected with PbA (PbA-CBA mice) demonstrated mild changes in vascular permeability as early as days 2-3, prior to the appearance on day 5 of cerebral symptoms, whereas mice with non-cerebral malaria did not show any vascular permeability changes until the very late stage of the disease (days 14-22). In the PbA infections, progressive deterioration of endothelial barrier properties, demonstrated by Evans' Blue leakage both generally and from specific focal areas, as well as a developing monocytosis and adherence of mononuclear cells to the endothelium of the retinal vessels continued until death (in CBA/T6 mice) or resolution (in DBA/2J mice). Adherent monocytes, particularly in PbA-CBA mice, were associated with reduced Hoechst staining of individual endothelial cells and a banking up proximally of both parasitized and non-parasitized blood cells in the small blood vessels, often with accompanying focal leakage of Evans' Blue from the retinal vessels. The occurrence and severity of these early changes in the microcirculation correlated with the subsequent development of cerebral symptoms. Monocyte margination appeared to be the most significant factor associated with the development of cerebral symptoms.
Insights
Murine cerebral malaria involves early microvascular changes, including increased permeability and monocyte adhesion in retinal vessels. These factors correlate with symptom development and severity, offering insights into cerebral malaria pathology.
Area of Science:
- Immunology
- Pathology
- Neuroscience
Background:
- Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection.
- Murine models are crucial for understanding CM pathogenesis.
- Distinct Plasmodium berghei ANKA (PbA) and P. berghei K173 (Pb) strains induce different malaria outcomes in mice.
Purpose of the Study:
- To investigate the early pathological factors contributing to murine cerebral malaria.
- To elucidate the role of microvascular changes in CM development using specific mouse and parasite strains.
- To correlate early retinal microcirculatory events with the onset of cerebral symptoms.
Main Methods:
- Utilized CBA/T6 and DBA/2J mouse strains infected with PbA or Pb.
- Employed the retinal whole-mount technique to visualize microvascular alterations.
- Assessed vascular permeability using Evans' Blue leakage.
- Monitored monocyte behavior and endothelial cell changes via microscopy and Hoechst staining.
Main Results:
- PbA-infected CBA/T6 mice developed fatal CM, while DBA/2J mice had non-fatal CM.
- Early vascular permeability changes (days 2-3) were observed in PbA-infected CBA/T6 mice preceding cerebral symptoms.
- Progressive endothelial barrier dysfunction, monocyte adherence, and microvascular leakage occurred in PbA infections.
- Monocyte margination in retinal vessels strongly correlated with the development and severity of cerebral symptoms.
Conclusions:
- Early microvascular changes, particularly monocyte margination and endothelial barrier disruption, are critical determinants of cerebral malaria development.
- The retinal whole-mount technique provides valuable insights into the early pathogenesis of murine CM.
- Understanding these early events can inform therapeutic strategies for cerebral malaria.