The Liver-Stage Plasmodium Infection Is a Critical Checkpoint for Development of Experimental Cerebral Malaria

Abstract

Cerebral malaria is a life-threatening complication of malaria in humans, and the underlying pathogenic mechanisms are widely analyzed in a murine model of experimental cerebral malaria (ECM). Here, we show abrogation of ECM by hemocoel sporozoite-induced infection of a transgenic Plasmodium berghei line that overexpresses profilin, whereas these parasites remain fully virulent in transfusion-mediated blood infection. We, thus, demonstrate the importance of the clinically silent liver-stage infection for modulating the onset of ECM. Even though both parasites triggered comparable splenic immune cell expansion and accumulation of antigen-experienced CD8+ T cells in the brain, infection with transgenic sporozoites did not lead to cerebral vascular damages and suppressed the recruitment of overall lymphocyte populations. Strikingly, infection with the transgenic strain led to maintenance of CD115+Ly6C+ monocytes, which disappear in infected animals prone to ECM. An early induction of IL-10, IL-12p70, IL-6, and TNF at the time when parasites emerge from the liver might lead to a diminished induction of hepatic immunity. Collectively, our study reveals the essential role of early host interactions in the liver that may dampen the subsequent pro-inflammatory immune responses and influence the occurrence of ECM, highlighting a novel checkpoint in this fatal pathology.

Multistage antiplasmodial activity of hydroxyethylamine compounds, in vitro and in vivo evaluations

“…Since the parasite density is very low in the liver stage as compared to other developmental stages, this represents one of the potential targets for the antimalarial drugs that prohibit blood-stage infection and subsequent transmission to mosquitoes can also be quenched. [27][28][29] Therefore, HepG2 cells infected P. berghei sporozoites were treated at 1, 10 and 100 mM concentrations of both the compounds in culture. The parasite load was systematically quantied in control and the treated cells.…”

γδ T cells in malaria: a double‐edged sword

“…The vast majority of the studies using the ECM model have challenged the mice with P. berghei-pRBC, a route of infection that bypasses the liver stage of Plasmodium infection, thus neglecting the potential impact of the liver stage in the subsequent (erythrocytic and symptomatic phase) of Plasmodium infection and in CM pathogenesis. In fact, very few studies have shown that pre-erythrocytic or early immune responses may modulate downstream immune responses and thereby impact ECM development or clinical symptoms, respectively, in mice and in humans [26,[51][52][53][54][55][56]. Some of these studies used chemical or genetically modified P. berghei ANKA parasites that after Spz infection showed impaired development during liver and intraerythrocytic stages, thus impacting on subsequent systemic immune responses and, ultimately, on ECM development [53,54].…”

“…Some of these studies used chemical or genetically modified P. berghei ANKA parasites that after Spz infection showed impaired development during liver and intraerythrocytic stages, thus impacting on subsequent systemic immune responses and, ultimately, on ECM development [53,54]. By contrast, another study with a transgenic P. berghei ANKA parasite that moderately overexpress profilin, an immunomodulatory protein, and that after Spz infection did not show evident developmental impairments, induced an early production of the regulatory cytokine interleukin (IL)-10 and pro-inflammatory cytokines, such as IL-12p70, IL-6, and TNF [56]. This early immune response seemed to dampen the subsequent pro-inflammatory responses during blood stage and prevented the development of ECM [56].…”

“…By contrast, another study with a transgenic P. berghei ANKA parasite that moderately overexpress profilin, an immunomodulatory protein, and that after Spz infection did not show evident developmental impairments, induced an early production of the regulatory cytokine interleukin (IL)‐10 and pro‐inflammatory cytokines, such as IL‐12p70, IL‐6, and TNF [56]. This early immune response seemed to dampen the subsequent pro‐inflammatory responses during blood stage and prevented the development of ECM [56]. Notably, this transgenic parasite induced lower sterile immunity in the context of immunization studies when compared with wild‐type (WT) parasites, suggesting reduced hepatic immune responses [56].…”

“…This early immune response seemed to dampen the subsequent pro‐inflammatory responses during blood stage and prevented the development of ECM [56]. Notably, this transgenic parasite induced lower sterile immunity in the context of immunization studies when compared with wild‐type (WT) parasites, suggesting reduced hepatic immune responses [56]. It would be interesting to assess the functional interaction of γδ T cells with this transgenic parasite in the context of whole‐Spz vaccination strategies.…”