Papel do interferon do tipo I em neutrófilos durante a malária

Abstract

The complexity of parasite-host interactions and the limited knowledge of the mechanisms by which Plasmodium spp. trigger innate immune cells are the main impediments in understanding the pathogenesis of malaria. Neutrophils are the most abundant leukocyte population in the bloodstream, a main site of Plasmodium sp. infection. Yet, the role of these polymorphonuclear cells in mediating either resistance or pathogenesis of malaria is poorly understood. Here, we report that malaria patients display higher levels of plasma cytokines and although we found an increased number of circulating neutrophils in malaria patients, they are not responsible for this elevated production. We show that monocytes are the primary source of cytokines during P. vivax infection. Besides that, we demonstrated that neutrophils from malaria patients are highly activated, as indicated by type I interferon transcription signature, increased expression of surface activation markers, myeloperoxidase and release of reactive oxygen species, as well as high frequency of low-density granulocytes subpopulation. In humans, the activation of neutrophils was associated with increased levels of serum alanine and aspartate aminotransferases that indicate liver damage. In a rodent malaria model, we observed an intense recruitment of neutrophils to liver sinusoids. Neutrophil migration, caspase-1 activation, IL-1 and chemokines expression as well as liver damage were all dependent on type I interferon signaling. Thus, type I interferon has pivotal role in neutrophil activation and malaria pathogenesis.