Fluctuations of Spleen Cytokine and Blood Lactate, Importance of Cellular Immunity in Host Defense Against Blood Stage Malaria Plasmodium yoelii

Abstract

Our previous studies of protective immunity and pathology against blood stage malaria parasites have shown that not only CD4+ T cells, but also CD8+ T cells and macrophages, are important for host defense against blood stage malaria infection. Furthermore, we found that Plasmodium yoelii 17XNL (PyNL) parasitizes erythroblasts, the red blood cell (RBC) precursor cells, which then express MHC class I molecules. In the present study, we analyzed spleen cytokine production. In CD8+ T cell-depleted mice, IL-10 production in early stage infection was increased over two-fold relative to infected control animals and IL-10+ CD3− cells were increased, whereas IFN-γ production in the late stage of infection was decreased. At day 16 after PyNL infection, CD8+ T cells produced more IFN-γ than CD4+ T cells. We evaluated the involvement of the immunoproteasome in induction of immune CD8+ T cells, and the role of Fas in protection against PyNL both of which are downstream of IFN-γ. In cell transfer experiments, at least the single molecules LMP7, LMP2, and PA28 are not essential for CD8+ T cell induction. The Fas mutant LPR mouse was weaker in resistance to PyNL infection than WT mice, and 20% of the animals died. LPR-derived parasitized erythroid cells exhibited less externalization of phosphatidylserine (PS), and phagocytosis by macrophages was impaired. Furthermore, we tried to identify the cause of death in malaria infection. Blood lactate concentration was increased in the CD8+ T cell-depleted PyNL-infected group at day 19 (around peak parasitemia) to similar levels as day 7 after infection with a lethal strain of Py. When we injected mice with lactate at day 4 and 6 of PyNL infection, all mice died at day 8 despite demonstrating low parasitemia, suggesting that hyperlactatemia is one of the causes of death in CD8+ T cell-depleted PyNL-infected mice. We conclude that CD8+ T cells might control cytokine production to some extent and regulate hyperparasitemia and hyperlactatemia in protection against blood stage malaria parasites.

Potential and Limitations of Cross-Protective Vaccine against Malaria by Blood-Stage Naturally Attenuated Parasite

“…First, we considered the administration of our blood-stage naturally attenuated parasite vaccine in immunocompromised individuals. To model this scenario, we immunized several immunodeficient mice, either immune cell depleted or with mutated/knocked out immune molecules, with PyNL ( Table 1 and [ 26 , 28 , 29 ]). There were three expected phenotypes based on the requirement for controlling PyNL infection; 1, if the molecules or cells were essential for protection, all PyNL-infected mice would die.…”

“…We have previously analyzed the protective role of T cells or immunological molecules, or both, against blood stage malaria [ 26 , 28 , 29 ], and found CD4 and CD8 T cells to be important but not essential for protection against primary infection with blood-stage PyNL ( Table 1 ) [ 26 ]. T cells and B cells possess immunological memory so induction of pathogen-specific memory cells is essential for sterile protection against malaria.…”

“…Our group has studied protective immunity and pathology in blood-stage malaria [ 25 , 26 , 27 , 28 , 29 ]. In this study, we aimed to model the blood-stage human malaria parasite in individuals in malaria non-endemic areas using the mouse blood-stage malaria infection model.…”

B cell intrinsic expression of IFNλ receptor suppresses the acute humoral immune response to experimental blood-stage malaria

“…The cell type responsible for IFNλ-mediated alterations in the CD4+ T cell response during blood-stage malaria infection should be a focus of further investigations. Because conflicting evidence exists regarding the role of CD8 + T cells during experimental acute blood stage malaria [86][87][88][89][90][91], we did not investigate the role of the CD8 + T cell population in our model. As other groups have reported increased numbers of CD8+ T cells in Ifnlr1 −/mice during the acute response to LCMV, [41], there could be a potential role for alterations in the CD8+ T cell population in Ifnlr1 −/mice.…”

Live Vaccination with Blood-Stage Plasmodium yoelii 17XNL Prevents the Development of Experimental Cerebral Malaria

“…In an effort to gain fundamental knowledge about new vaccine technologies and prevent disease progression, our group has been studying the protective immunity and pathology of malaria using a murine malaria model [ 23 , 24 , 25 , 26 , 27 , 28 ]. Since CD4-positive T (CD4T) cells and CD8-positive T (CD8T) cells have immunological memory and provide the principle of the mode of action of the vaccine, it is important to determine their role in malaria.…”