Mechanistic insights into immunopathogenesis of murine cerebral malaria: Cues from ?young? C57BL/6J and BALB/c mice

Cerebral malaria (CM), a major cause of mortality in children <5 years, presents disparity in pathophysiological features and poor prognosis compared to adults. Adult C57BL/6J mice infected with Plasmodium berghei ANKA (PbA) are widely used to understand CM pathogenesis compared to relatively less prone BALB/c mice; however, age and immune status of the host also influence disease sequelae and cerebral manifestations. Murine models of CM known so far do not project complete disease spectrum of pediatric CM. The present study was designed to dissect and differentiate CM immunopathogenesis in young BALB/c and C57BL/6J mice infected with PbA, in search of a competent mouse model mimicking pediatric CM. Multipronged approach including the analysis of blood-brain barrier (BBB) permeability and parasite infiltration, histopathology, nitric oxide levels, and pro/antiinflammatory (TNF-alpha, IFN-gamma, IL-4, and IL-10) cytokine expression were compared in the cortices of both young BALB/c and C57BL/6J mice. The results illustrate severe course of infection and typical CM like histopathological alterations including monocytic plugging in PbA-infected young BALB/c compared to C57BL/6J mice. The decreased expression of tight junction proteins (ZO-1 and Claudin-3) and Evan's blue extravasation was also more evident in BALB/c mice indicating a more permeable BBB. The increased cortical expression of TNF-alpha, IFN gamma, IL-4, IL-10, iNOS, eNOS, nNOS, and associated activation of brain resident cells in cortices of BALB/c with progressive parasitaemia depicts the cumulative involvement of host immune responses and parasite accumulation in progression of CM. Thus, the incongruity of cytokine balance resulted in worsening of disease manifestation in young BALB/c similar to pediatric CM.

Automated summary

This study aimed to dissect and differentiate the immunopathogenesis of cerebral malaria in young BALB/c and C57BL/6J mice infected with Plasmodium berghei ANKA (PbA), in search of a mouse model mimicking pediatric cerebral malaria. The results showed that young BALB/c mice had a severe course of infection and typical histopathological alterations, such as monocytic plugging, compared to C57BL/6J mice. BALB/c mice also exhibited decreased blood-brain barrier permeability and increased expression of pro/anti-inflammatory cytokines. These findings suggest that the imbalance of cytokine expression contributes to the worsening of disease manifestation in young BALB/c mice, similar to pediatric cerebral malaria.