Abstract
BackgroundTo date all efforts to develop a malaria vaccine have failed, reflecting the still fragmentary knowledge about protective mechanisms against malaria. In order to evaluate if vaccination changes responses of the anti-malaria effectors spleen and liver to blood stage malaria, BALB/c mice succumbing to infection with Plasmodium chabaudi were compared to those surviving after vaccination.MethodsMice were vaccinated with host cell plasma membranes isolated from P. chabaudi-infected erythrocytes. Hepatic and splenic capacity to trap particulate material was determined after injection of fluorescent polystyrol beads. Hepatic gene expression was measured using real-time RT-PCR and Northern blotting.ResultsSurvival of BALB/c mice was raised from 0% to 80% and peak parasitaemia was decreased by about 30% by vaccination. Vaccination boosted particle trapping capacity of the liver during crisis when splenic trapping is minimal due to spleen 'closing'. It also attenuated malaria-induced inflammation, thus diminishing severe damages and hence liver failure. Vaccination increased hepatic IFN-γ production but mitigated acute phase response. Vaccination has a complex influence on infection-induced changes in expression of hepatic nuclear receptors (CAR, FXR, RXR, and PXR) and of the metabolic enzymes Sult2a and Cyp7a1. Although vaccination decreased CAR mRNA levels and prevented Cyp7a1 suppression by the CAR ligand 1,2-bis [2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on day 8 p.i., Sult2a-induction by TCPOBOP was restored.ConclusionThese data support the view that the liver is an essential effector site for a vaccine against blood stage malaria: vaccination attenuates malaria-induced inflammation thus improving hepatic metabolic activity and particle trapping activity of the liver.
Highlights
To date all efforts to develop a malaria vaccine have failed, reflecting the still fragmentary knowledge about protective mechanisms against malaria
In an experimental malaria model, Plasmodium chabaudi in rodents, a vaccination model has been previously developed that resembles natural immunity in so far that it helps susceptible mice to survive an otherwise lethal blood stage infection without preventing parasitaemia [4]. This vaccination model uses host cell plasma membranes of P. chabaudi-parasitized red blood cells as an immunogen. These erythrocyte membranes contain several parasite proteins [5,6] the functions of which have remained unknown to date, including a major immunogenic P. chabaudi protein Pc90 against which most of the antibodies induced by this type of vaccination are directed [4]
Female BALB/c mice are highly susceptible to P. chabaudi malaria
Summary
To date all efforts to develop a malaria vaccine have failed, reflecting the still fragmentary knowledge about protective mechanisms against malaria. In an experimental malaria model, Plasmodium chabaudi in rodents, a vaccination model has been previously developed that resembles natural immunity in so far that it helps susceptible mice to survive an otherwise lethal blood stage infection without preventing parasitaemia [4] This vaccination model uses host cell plasma membranes of P. chabaudi-parasitized red blood cells (pRBC) as an immunogen. These erythrocyte membranes contain several parasite proteins [5,6] the functions of which have remained unknown to date, including a major immunogenic P. chabaudi protein Pc90 against which most of the antibodies induced by this type of vaccination are directed [4] This vaccination model is used here to further study the effector sites and mechanisms, which have to be activated to survive blood stage infections
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