Abstract
BackgroundInfection with Plasmodium berghei ANKA (PbA) in susceptible mice induces a syndrome called experimental cerebral malaria (ECM) with severe pathologies occurring in various mouse organs. Immune mediators such as T cells or cytokines have been implicated in the pathogenesis of ECM. Red blood cells infected with PbA parasites have been shown to accumulate in the brain and other tissues during infection. This accumulation is thought to be involved in PbA–induced pathologies, which mechanisms are poorly understood.Methods and FindingsUsing transgenic PbA parasites expressing the luciferase protein, we have assessed by real-time in vivo imaging the dynamic and temporal contribution of different immune factors in infected red blood cell (IRBC) accumulation and distribution in different organs during PbA infection. Using deficient mice or depleting antibodies, we observed that CD8+ T cells and IFN-γ drive the rapid increase in total parasite biomass and accumulation of IRBC in the brain and in different organs 6–12 days post-infection, at a time when mice develop ECM. Other cells types like CD4+ T cells, monocytes or neutrophils or cytokines such as IL-12 and TNF-α did not influence the early increase of total parasite biomass and IRBC accumulation in different organs.ConclusionsCD8+ T cells and IFN-γ are the major immune mediators controlling the time-dependent accumulation of P. berghei-infected red blood cells in tissues.
Highlights
Malaria remains one of the most health-threatening diseases worldwide and is a major global cause of morbidity and mortality, with,800 000 deaths worldwide each year [1,2]
It has been reported that some patients clinically diagnosed with human cerebral malaria had little or no infected red blood cell (IRBC) sequestered in their brain capillaries [11,12], suggesting that IRBC sequestration might not be sufficient per se to cause CM
RAG22/2 mice infected with PbAluc did not develop experimental cerebral malaria (ECM) contrary to wild-type (WT) C57BL/6J mice which died with neurological signs 6 to 12 days post-infection (Figure 1A)
Summary
Malaria remains one of the most health-threatening diseases worldwide and is a major global cause of morbidity and mortality, with ,800 000 deaths worldwide each year [1,2]. The immunological hypothesis is based on the findings that i) a strong inflammatory response, characterized by elevated levels of pro-inflammatory cytokines [13,14], is observed during the acute phase of P. falciparum infection and ii) leukocytes and platelets, together with IRBC, were found sequestered intravascularly in the brain microvessels of CM patients [15,16], and in other organs such as the lungs [11]. Infection with Plasmodium berghei ANKA (PbA) in susceptible mice induces a syndrome called experimental cerebral malaria (ECM) with severe pathologies occurring in various mouse organs. Immune mediators such as T cells or cytokines have been implicated in the pathogenesis of ECM. This accumulation is thought to be involved in PbA–induced pathologies, which mechanisms are poorly understood
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