Common Strategies To Prevent and Modulate Experimental Cerebral Malaria in Mouse Strains with Different Susceptibilities

Abstract

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection, predominantly experienced by children and nonimmune adults, which results in significant mortality and long-term sequelae. Previous studies have reported distinct susceptibility gene loci in CBA/CaH (CBA) and C57BL/6 (B6) mice with experimental CM (ECM) caused by infection with Plasmodium berghei ANKA. Here we present an analysis of genome-wide expression profiles in brain tissue taken from B6 and CBA mice with ECM and report significant heterogeneity between the two mouse strains. Upon comparison of the leukocyte composition of ECM brain tissue, microglia were expanded in B6 mice but not CBA mice. Furthermore, circulating levels of gamma interferon, interleukin-10, and interleukin-6 were significantly higher in the serum of B6 mice than in that of CBA mice with ECM. Two therapeutic strategies were applied to B6 and CBA mice, i.e., (i) depletion of regulatory T (Treg) cells prior to infection and (ii) depletion of CD8؉ T cells after the establishment of ECM. Despite the described differences between susceptible mouse strains, depletion of Treg cells before infection attenuated ECM in both B6 and CBA mice. In addition, the depletion of CD8 ؉ T cells when ECM symptoms are apparent leads to abrogation of ECM in B6 mice and a lack of progression of ECM in CBA mice. These results may have important implications for the development of effective treatments for human CM.

High Parasite Burdens Cause Liver Damage in Mice following Plasmodium berghei ANKA Infection Independently of CD8+T Cell-Mediated Immune Pathology

“…Mice were monitored twice daily after day 5 postinfection (p.i. ), and clinical ECM was evaluated (3,4,31). Clinical ECM scores were defined by the presentation of the following signs: ruffled fur, hunching, wobbly gait, limb paralysis, convulsions, and coma.…”

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

“…Regulatory T cells can be beneficial or detrimental to the induction of ECM depending on the method and timing of regulatory T cell depletion and the genetic background of the host (17)(18)(19)(20)(21)(22)(23)(24). Th17 cells, which induce tissue inflammation and are capable of disrupting the blood brain barrier (25), do not appear to contribute to the pathogenesis of ECM (26).…”

Granzyme B Expression by CD8+ T Cells Is Required for the Development of Experimental Cerebral Malaria

“…It has been shown that parasite-specific CD8 + T cells are primed by conventional dendritic cells in the spleen and that these cells are found in the brain at the onset of neurologic disease (17)(18)(19)(20). Furthermore, depletion of these cells from clinically ill mice completely protects against disease, showing that CD8 + T cells mediate end-stage immune pathology in ECM (17,18,21), although the specific molecules produced by these cells in vivo to cause cerebral disease have not been clearly defined. In a study by Nitcheu et al (22), CD8 + T cells were harvested from infected, perforindeficient mice and transferred into rag2 2/2 mice.…”