Abstract
BackgroundThe role of the liver for survival of blood-stage malaria is only poorly understood. In experimental blood-stage malaria with Plasmodium chabaudi, protective vaccination induces healing and, thus, survival of otherwise lethal infections. This model is appropriate to study the role of the liver in vaccination-induced survival of blood-stage malaria.MethodsFemale Balb/c mice were vaccinated with a non-infectious vaccine consisting of plasma membranes isolated in the form of erythrocyte ghosts from P. chabaudi-infected erythrocytes at week 3 and week 1 before infection with P. chabaudi blood-stage malaria. Gene expression microarrays and quantitative real-time PCR were used to investigate the response of the liver, in terms of expression of mRNA and long intergenic non-coding (linc)RNA, to vaccination-induced healing infections and lethal P. chabaudi malaria at early patency on day 4 post infection, when parasitized erythrocytes begin to appear in peripheral blood.ResultsIn vaccination-induced healing infections, 23 genes were identified to be induced in the liver by > tenfold at p < 0.01. More than one-third were genes known to be involved in erythropoiesis, such as Kel, Rhag, Ahsp, Ermap, Slc4a1, Cldn13 Gata1, and Gfi1b. Another group of > tenfold expressed genes include genes involved in natural cytotoxicity, such as those encoding killer cell lectin-like receptors Klrb1a, Klrc3, Klrd1, the natural cytotoxicity-triggering receptor 1 Ncr1, as well as the granzyme B encoding Gzmb. Additionally, a series of genes involved in the control of cell cycle and mitosis were identified: Ccnb1, Cdc25c, Ckap2l were expressed > tenfold only in vaccination-protected mice, and the expression of 22 genes was at least 100% higher in vaccination-protected mice than in non-vaccinated mice. Furthermore, distinct lincRNA species were changed by > threefold in livers of vaccination-protected mice, whereas lethal malaria induced different lincRNAs.ConclusionThe present data suggest that protective vaccination accelerates the malaria-induced occurrence of extramedullary erythropoiesis, generation of liver-resident cytotoxic cells, and regeneration from malaria-induced injury in the liver at early patency, which may be critical for final survival of otherwise lethal blood-stage malaria of P. chabaudi.
Highlights
The role of the liver for survival of blood-stage malaria is only poorly understood
Morbidity and mortality from malaria are caused by the blood stages of the malaria-causing agent, parasitic protozoans of the genus Plasmodium, which develop within host erythrocytes
Identification of malaria‐inducible genes in the liver of vaccinated and non‐vaccinated mice To identify malaria-induced vaccination-responsive genes in the liver at early patency, vaccinated and nonvaccinated Balb/c mice were concomitantly infected with P. chabaudi, and livers prepared from three vaccinated mice on day 4 pi (Vd4 group) were individually analysed with Agilent’s 8 × 60 K oligo microarrays for global gene expression in relation to those of three non-infected vaccinated mice on day 0 pi (Vd0 group)
Summary
The role of the liver for survival of blood-stage malaria is only poorly understood. In experimental blood-stage malaria with Plasmodium chabaudi, protective vaccination induces healing and, survival of other‐ wise lethal infections. This model is appropriate to study the role of the liver in vaccination-induced survival of bloodstage malaria. The liver is equipped with effective mechanisms for removing aberrant erythrocytes including Plasmodiuminfected erythrocytes [6,7,8,9,10,11]. Plasmodium chabaudi infection in mice is an appropriate model to study the effector functions of the liver against blood-stage malaria without interfering with the preceding liver-stages of malaria parasites [12, 13]. The P. chabaudi model shares several characteristics with P. falciparum, which causes about 99% of global malaria-related deaths in humans [1]
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