IL-1α promotes liver inflammation and necrosis during blood-stage Plasmodium chabaudi malaria.

Malaria causes hepatic inflammation and damage, which contribute to disease severity. The pro-inflammatory cytokine interleukin (IL)-1α is released by non-hematopoietic or hematopoietic cells during liver injury. This study established the role of IL-1α in the liver pathology caused by blood-stage P. chabaudi malaria. During acute infection, hepatic inflammation and necrosis were accompanied by NLRP3 inflammasome-independent IL-1α production. Systemically, IL-1α deficiency attenuated weight loss and hypothermia but had minor effects on parasitemia control. In the liver, the absence of IL-1α reduced the number of TUNEL+ cells and necrotic lesions. This finding was associated with a lower inflammatory response, including TNF-α production. The main source of IL-1α in the liver of infected mice was inflammatory cells, particularly neutrophils. The implication of IL-1α in liver inflammation and necrosis caused by P. chabaudi infection, as well as in weight loss and hypothermia, opens up new perspectives for improving malaria outcomes by inhibiting IL-1 signaling.

Malaria liver stage susceptibility locus identified on mouse chromosome 17 by congenic mapping.

Host genetic variants are known to confer resistance to Plasmodium blood stage infection and to control malaria severity both in humans and mice. This work describes the genetic mapping of a locus for resistance to liver stage parasite in the mouse. First, we show that decreased susceptibility to the liver stage of Plasmodium berghei in the BALB/c mouse strain is attributable to intra-hepatic factors and impacts on the initial phase of blood stage infection. We used QTL mapping techniques to identify a locus controlling this susceptibility phenotype (LOD score 4.2) on mouse chromosome 17 (belr1 locus). Furthermore, analysis of congenic mouse strains delimited the belr1 locus boundaries distally to the H2 region. Quantification of parasites in the liver of infected congenic mice strongly suggested that the belr1 locus represents a genetic factor controlling the expansion of P. berghei in the hepatic tissue. The mapping of belr1 locus raises the hypothesis that host gene variation is able to control the progression of Plasmodium liver stage infection and opens the possibility that the human genomic region orthologue to belr1 may contain genes that confer resistance to the human malaria liver stage.

Transcriptome profile of dendritic cells during malaria: cAMP regulation of IL-6.

Dendritic cells (DCs) have been proposed as mediators of immunity against malaria parasites, as well as a target for inhibition of cellular responses. Here we describe the transcriptomic analysis of spleen DCs in response to Plasmodium infection in a rodent model. We identified a high number of unique transcripts modulated in DCs upon infection. Many cellular functions suffer extensive genomic regulation including the cell cycle, the glycolysis and purine metabolism pathways and also defence responses. Only a small fraction of the regulated genes are coincident with the response induced by other pathogens, suggesting that Plasmodium induces a unique genetic re-programming of DCs. We confirmed regulation of a number of cytokines at the mRNA level including IL-6, IL-10 and IFN-gamma. We further dissected a signalling pathway regulating Plasmodium-induced expression of IL-6 by DCs, which is mediated by release of PGE2, increases in intracellular cAMP and activation of PKA and p38-MAPK.