Characterization of the population dynamics of the splenic subsets of monocytes, macrophages and dendritic cells during Plasmodium chabaudi AS infection.

Abstract

Introduction: Malaria is an infectious disease in which the immunological mechanisms that confer protection are also associated with the clinical manifestations of the disease. Innate and acquired immunity are important elements for the protection against malaria disease. Among the mechanisms of the innate immune response, monocytes, macrophages and dendritic cells (DCs) are crucial for the generation and development of the protective immunity to Plasmodium. The splenic macrophages and monocytes populations are highly heterogeneous and red pulp macrophages, inflammatory monocytes and DCs are the mainly populations involved in the innate response to malaria. Interactions of these phagocytic populations with the infected red blood cells (iRBCs) or parasite products are mediated by transmembrane or cytosolic receptors such as pathogen-associated molecular patterns (PAMPs; TLR and NLR) and phagocytic receptors (Fc³Rs, complement receptors and CD36), resulting in cellular activation. The iRBCs phagocytosis by different receptors can induce distinct activation profile in the macrophages populations, as well as inflammatory and resident monocytes are related respectively with the generation or differentiation of M1 and M2 macrophages. Furthermore, the activation profile of splenic macrophages can be altered during the infection, since in the acute phase there is a predominance of IFN-³, a cytokine responsible for the induction of a M1 profile in macrophages, while CD4+ T cells that secrete IFN-³ and IL-10 that are potentially able to induce regulatory or M2 macrophages can be found in the chronic phase.Statement of problem: In this context, it is not fully elucidated the dynamics of monocytes populations, macrophages and DCs during P. c. chabaudi AS infection.Experimental strategy: In order to characterize the dynamics of the splenic subsets of monocytes, macrophages and DCs, six scientific strategies will be used in the experimental model of P. c. chabaudi malaria: 1) To characterize the phenotype of the populations of macrophage, DCs and monocytes. 2) To evaluate the phagocytosis of the iRBC and the activation profile induced by the phagocytosis of the different populations of macrophages and monocytes. 3) To evaluate the profile of activation of the splenic macrophage during the early and late phases of infection. 4) To evaluate the profile of activation of the splenic macrophage from P. c. chabaudi AS infected mice treated with recombinant IFN-³ or anti- IFN-³ antibody and challenged or not with P. c. chabaudi AJ. 5) To determinate the genetic profile of the Ly6Chigh and Ly6Clow monocytes subtypes during infection. 6) To analyze the differentiation of the different subtypes of monocytes of the spleen in the populations of macrophages or DCs. Expected results: To determinate the dynamic of the monocytes subtypes, macrophages and DCs and the activation profile of the splenic macrophages acquired during the P. c. chabaudi infection.Expected contribution to the field: The elucidation of these aspects has important implications in the understanding of the balance between protection and pathology mediated by the innate immune system during the P. c. chabaudi infection, providing strategies for the development of vaccines or new drugs that help in malaria control through the modulation of these cells.Existing support: This study is fully consistent with the work being developed by our research group with the support of FAPESP (regular grant, scholarships for master and doctorate) and CNPq (productivity fellowship and Universal grant).