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Evidence for multiple pathologic and protective mechanisms of murine cerebral malaria
V M Jennings1, A A Lal, R L Hunter
1Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA. vaj7@cdc.gov
Abstract:
Murine cerebral malaria (CM) induced by Plasmodium berghei ANKA kills susceptible mice within 24 to 48 h of onset of symptoms and is characterized by the production of inflammatory cytokines in the brain. C57BL/6J mice are sensitive to lethal CM, while A/J mice are resistant. These strains of mice were immunized with an adjuvant vaccine of killed whole-blood-stage parasites. The immunization protected C57BL/6 mice from lethal CM following virulent challenge. The same immunization increased the incidence of lethal CM in A/J mice challenged similarly. Histopathologic examination of the brains of mice from these studies revealed two distinct types of lesions. Type I CM is acute in onset; usually lethal; and characterized by widespread microglial activation, endothelial cell damage, and microvascular disruption in the brain. Type II CM is characterized by intense, but focal, mononuclear cell inflammation without endothelial cell damage or microvascular destruction. Animals with type II lesions were clinically normal and protected from type I lesions. Available clinical, epidemiological, and biochemical evidence suggests that type I and type II lesions might exist in human CM as well.
Insights
Vaccinating mice against cerebral malaria (CM) protected susceptible strains but worsened outcomes in resistant strains, revealing two distinct lesion types. This suggests potential parallels in human cerebral malaria.
Area of Science:
- Immunology
- Pathology
- Infectious Diseases
Background:
- Murine cerebral malaria (CM) induced by Plasmodium berghei ANKA is a lethal condition characterized by brain inflammation.
- C57BL/6J mice are susceptible to lethal CM, while A/J mice are resistant.
Purpose of the Study:
- To investigate the effects of immunization with killed whole-blood-stage parasites on CM susceptibility in different mouse strains.
- To characterize the distinct histopathological lesions associated with CM.
Main Methods:
- Immunization of C57BL/6J (susceptible) and A/J (resistant) mice with an adjuvant vaccine of killed whole-blood-stage parasites.
- Virulent Plasmodium berghei ANKA challenge to assess CM.
- Histopathological examination of brain tissues to identify and classify lesions.
Main Results:
- Immunization protected C57BL/6 mice from lethal CM.
- The same immunization increased the incidence of lethal CM in A/J mice.
- Two distinct lesion types were identified: Type I (acute, lethal, widespread microglial activation, endothelial damage, microvascular disruption) and Type II (focal mononuclear inflammation, no endothelial damage).
- Mice with Type II lesions were clinically normal and protected from Type I lesions.
Conclusions:
- Vaccine-induced immune responses can differentially affect CM outcomes based on host genetic background.
- The identified Type I and Type II CM lesions may represent distinct pathological entities relevant to human cerebral malaria.
- Further research is warranted to explore the mechanisms underlying these distinct lesion types and their implications for human CM treatment and prevention.