No abstract

Malaria, caused by Plasmodium species (spp.), is a deadly parasitic disease that results in approximately 400,000 deaths per year globally. Autophagy pathways play a fundamental role in the developmental stages of the parasite within the mammalian host. They are also involved in the production of Plasmodium-derived extracellular vesicles (EVs), which play an important role in the infection process, either by providing nutrients for parasite growth or by contributing to the immunopathophysiology of the disease. For example, during the hepatic stage, Plasmodium-derived EVs contribute to parasite virulence by modulating the host immune response. EVs help in evading the different autophagy mechanisms deployed by the host for parasite clearance. During cerebral malaria, on the other hand, parasite-derived EVs promote an astrocyte-mediated inflammatory response, through the induction of a non-conventional host autophagy pathway. In this review, we will discuss the cross-talk between Plasmodium-derived microvesicles and autophagy, and how it influences the outcome of infection.

Many parasitic diseases (including cerebral malaria, human African trypanosomiasis, cerebral toxoplasmosis, neurocysticercosis and neuroschistosomiasis) feature acute or chronic brain inflammation processes, which are often associated with deregulation of glial cell activity and disruption of the brain blood barrier’s intactness. The inflammatory responses of astrocytes and microglia during parasite infection are strongly influenced by a variety of environmental factors. Although it has recently been shown that the gut microbiota influences the physiology and immunomodulation of the central nervous system in neurodegenerative diseases like Alzheimer’s disease and Parkinson’s, the putative link in parasite-induced neuroinflammatory diseases has not been well characterized. Likewise, the central nervous system can influence the gut microbiota. In parasite infections, the gut microbiota is strongly perturbed and might influence the severity of the central nervous system inflammation response through changes in the production of bacterial metabolites. Here, we review the roles of astrocytes and microglial cells in the neuropathophysiological processes induced by parasite infections and their possible regulation by the gut microbiota.

Interleukin-33 (IL-33) is an immunomodulatory cytokine which plays critical roles in tissue function and immune-mediated diseases. IL-33 is abundant within the brain and spinal cord tissues where it acts as a key cytokine to coordinate the exchange between the immune and central nervous system (CNS). In this review, we report the recent advances to our knowledge regarding the role of IL-33 and of its receptor ST2 in cerebral malaria, and in particular, we highlight the pivotal role that IL-33/ST2 signaling pathway could play in brain and cerebrospinal barriers permeability. IL-33 serum levels are significantly higher in children with severe Plasmodium falciparum malaria than children without complications or noninfected children. IL-33 levels are correlated with parasite load and strongly decrease with parasite clearance. We postulate that sequestration of infected erythrocytes or merozoites liberation from schizonts could amplify IL-33 production in endothelial cells, contributing either to malaria pathogenesis or recovery.

Malaria is associated with complicated immunopathogenesis. In this study, we provide evidence for an unexpected role of TLR3 in promoting the establishment of Plasmodium yoelii infection through delayed clearance of parasitemia in wild type C57BL/6jRj (B6) compared with TLR3 knockout mice. In this study, we confirmed an increased expression of Tlr3, Trif, Tbk1, and Irf7/Irf3 in the liver 42 h postinfection and the initiation of an early burst of proinflammatory response such as Ifng, NF-kB, and Tnfa in B6 mice that may promote parasite fitness. Interestingly, in the absence of TLR3, we showed the involvement of high IFN-g and lower type I IFN response in the early clearance of parasitemia. In parallel, we observed an increase in splenic NK and NKT cells expressing TLR3 in infected B6 mice, suggesting a role for TLR sensing in the innate immune response. Finally, we find evidence that the increase in the frequency of CD19 + TLR3 + B cells along with reduced levels of total IgG in B6 mice possibly suggests the initiation of TLR3-dependent pathway early during P. yoelii infection. Our results thus reveal a new mechanism in which a parasite-activated TLR3 pathway promotes blood stage infection along with quantitative and qualitative differences in Ab responses.