MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice

Abstract

The deadliest complication of Plasmodium falciparum infection is cerebral malaria (CM), with a case fatality rate of 15 to 25% in African children despite effective antimalarial chemotherapy. No adjunctive treatments are yet available for this devastating disease. We previously reported that the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) rescued mice from experimental CM (ECM) when administered late in the infection, a time by which mice had already suffered blood–brain barrier (BBB) dysfunction, brain swelling, and hemorrhaging. Herein, we used longitudinal MR imaging to visualize brain pathology in ECM and the impact of a new DON prodrug, JHU-083, on disease progression in mice. We demonstrate in vivo the reversal of disease markers in symptomatic, infected mice following treatment, including the resolution of edema and BBB disruption, findings usually associated with a fatal outcome in children and adults with CM. Our results support the premise that JHU-083 is a potential adjunctive treatment that could rescue children and adults from fatal CM.

CD8+ T cells target cerebrovasculature in children with cerebral malaria

“…An existing mouse model for CM, experimental CM (ECM), shares many features with the human disease. Indeed, several studies using a variety of imaging modalities, including MRI, provided evidence of vasogenic brain swelling, BBB dysfunction, and fatal brainstem herniation in ECM (29)(30)(31)(32), similar to observations in children with CM by MRI (12,33). However, the mouse model suggests an alternative mechanism of pathology.…”

“…Examples of low to no sequestration (Seq lo or Seq 0 ) are given for CM + HIV -, CM -HIV -, and CM -HIV + children, respectively (Supplemental Figure 1, C-E). Collectively, CM status, iRBC sequestration levels, and HIV status were used to define 6 groups of children ( Figure 1 and Table 1 [31][32][33][34]. The majority of the samples analyzed were collected by the Blantyre Malaria Project (BMP) (see Methods); however, the CM -Seq 0 HIVgroup also included samples acquired from the Human Brain Collection Core (HBCC) (see Methods and Supplemental Table 2).…”

“…Asterisks denote statistical significance: FDR *P ≤ 0.05; ***P ≤ 0.001. tavascular distribution of CD8 + T cells in children perfectly mirrored the distribution observed in the mouse model of CM. Given these observations, it is encouraging that drugs that target T cells have proven effective in preventing and even reversing ECM in mice (29,32,43). We demonstrated that the glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON), which targets the metabolism of activated T cells, is highly efficacious in treating mice late in the disease, when it has progressed to a point where significant brain swelling and BBB dysfunction have occurred (32,43).…”

“…Given these observations, it is encouraging that drugs that target T cells have proven effective in preventing and even reversing ECM in mice (29,32,43). We demonstrated that the glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON), which targets the metabolism of activated T cells, is highly efficacious in treating mice late in the disease, when it has progressed to a point where significant brain swelling and BBB dysfunction have occurred (32,43). Another adjunctive therapy for CM was suggested by our finding that blocking vascular adhesion of CD8 + T cells in the brains of mice using VLA-4-and LFA-1-specific antibodies rescued mice from late-stage ECM (29,44).…”

Testing the impact of a single nucleotide polymorphism in a Plasmodium berghei ApiAP2 transcription factor on experimental cerebral malaria in mice

“…An important tool for the study of CM is the mouse model of CM, namely experimental CM (ECM). ECM is induced by infection of susceptible mouse strains such as C57BL/6 with the ECM-causing rodent Plasmodium strain, PbANKA that recapitulates many of the features of CM in children both clinically and pathologically [7][8][9][10][11][12][13][14] . PbANKA infection results in the rapid progression of disease, leading to development of as ataxia, paralysis and coma accompanied by brain hemorrhages, iRBC sequestration in brain vessels, edema, and if left untreated, within 5-7 days post infection, death, likely by neuronal cell death in the brain stem 11,12 .…”