SUSTAINED SYSTEMIC AND NEUROINFLAMMATION IN COGNITIVE DYSFUNCTIONAL FEMALE MICE AFTER NON-SEVERE EXPERIMENTAL MALARIA
Plasmodial infection induces systemic inflammation with great potential to contribute to the development of severe illness and lethality. It is known that the hippocampus and cortex both play a pivotal role in memory processes and are affected by the neuroinflammation associated with cerebral malaria that causes long-lasting cognitive and behavioral sequelae. Since these sequelae are also associated with the non-severe form of malaria, it is important to correlate brain morphology, particularly glial cell involvement, and neuroimmune and neuroinflammatory features with memory acquisition and consolidation processes, in this clinical presentation of malaria, the most frequent worldwide. Here, we aimed to investigate cellular and molecular neuroimmune aspects of non-severe experimental malaria-associated cognitive dysfunction. Female C57BL/6 mice were infected with Plasmodium berghei ANKA and treated with chloroquine before any clinical signs of cerebral malaria emerged. No histopathological alteration, in hematoxylin-eosin staining, or axonal damage, in Bielschowskys silver-impregnated brain sections, was observed. However, morphological alterations in GFAP+ and Iba-1+ cells suggest that: i) astrocytes in the hippocampal dentate gyrus and the cornu Ammonis 1 regions and ii) microglia in the cornu Ammonis 1 region are responding to infection. Curiously, the effect persisted only in Iba-1+ cells up to 22 days post-infection. An increase in pro-inflammatory cytokines levels and expression was observed, in both the prefrontal cortex and the hippocampus. Also, serum and spleen cytokine levels were increased at 4 days post-infection. At 22 days post-infection, infected and treated mice showed an increase in serum cytokine levels that had homeostatic levels at 155 days post-infection. This dynamic points to both an immune stimulus persistence and a cytokine autoregulation post-infection. Infected mice exhibited acquisition and consolidation memory deficits in behavioral tests early after treatment (22 days post-infection). In conclusion, in a context of sustained systemic inflammation, mild neuroinflammatory alterations of glial cells may be involved in cognitive sequelae following a single episode of non-severe experimental malaria.