Resistance to Malaria by Enhanced Phagocytosis of Erythrocytes in LMP7-deficient Mice

Abstract

General cellular functions of proteasomes occur through protein degradation, whereas the specific function of immunoproteasomes is the optimization of antigen processing associated with MHC class I. We and others previously reported that deficiency in subunits of immunoproteasomes impaired the activation of antigen-specific CD8+ T cells, resulting in higher susceptibility to tumor and infections. We demonstrated that CD8+ T cells contributed to protection against malaria parasites. In this study, we evaluated the role of immunoproteasomes in the course of infection with rodent malaria parasites. Unexpectedly, Plasmodium yoelii infection of mice deficient in LMP7, a catalytic subunit of immunoproteasomes, showed lower parasite growth in the early phase of infection and lower lethality compared with control mice. The protective characteristics of LMP7-deficient mice were not associated with enhanced immune responses, as the mutant mice showed comparable or diminished activation of innate and acquired immunity. The remarkable difference was observed in erythrocytes instead of immune responses. Parasitized red blood cells (pRBCs) purified from LMP7-deficient mice were more susceptible to phagocytosis by macrophages compared with those from wild-type mice. The susceptibility of pRBC to phagocytosis appeared to correlate with deformity of the membrane structures that were only observed after infection. Our results suggest that RBCs of LMP7-deficient mice were more likely to deform in response to infection with malaria parasites, presumably resulting in higher susceptibility to phagocytosis and in the partial resistance to malaria.

Cytotoxic activities of CD8+ T cells collaborate with macrophages to protect against blood-stage murine malaria

“…In line with previous reports from ourselves and others on the importance of the phagocytosis of infected RBCs in the protective response to blood-stage malaria ( Zhang et al, 1999 ; Couper et al, 2007 ; Imai et al, 2010 ; Matsuzaki-Moriya et al, 2011 ; Duan et al, 2013 ), mice depleted of macrophages by administration with clodronate/liposome (C/L) quickly died in association with high parasitemia ( Figure 7A,B ). It has also been reported that PS-exposing cells are highly susceptible to phagocytosis by macrophages ( Fadok et al, 1998 ; van den Eijnde et al, 1998 ).…”

The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis

“…In a Leishmania major infection model, the absence of the subunit LMP7 had no effect on the ability of DCs to stimulate CD8 + T cells in both WT and LMP7 -/mice, as well as the authors showed similar IFNg production and T cell proliferation (51). The role of LMP7 was further highlighted in a malaria infection model, since the absence of LMP7 resulted in lower parasite growth, reduced parasite burden but an enhanced immune response with increased phagocytosis activity (52). LMP7 -/mice displayed reduced MHC I expression on APCs (53) and infected LMP2 -/mice showed a strong reduction (~70%) of CD8 + lymphocytes compared to WT mice (54).…”

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

“…Antibodies specific for parasite antigens and phagocytes play a major role in disrupting the erythrocytic cycle. Phagocytes, such as macrophages, engulf parasites and parasitized RBCs, and are required for the final clearance of malaria parasites [ 23 , 26 , 28 , 49 , 50 ]. Many studies have emphasized the role of antibodies in controlling parasitemia, and almost all malaria vaccines aim to induce specific antibodies [ 51 , 52 , 53 ].…”