Project description:The role of the liver for survival of blood-stage malaria is only fragmentary understood. In the experimental blood-stage malaria Plasmodium chabaudi, protective vaccination induces self-healing and, thus, survival of otherwise lethal infections. This study investigates the response of the liver, in terms of mRNA and lincRNA expression, to vaccination-induced self-healing infections and lethal P. chabaudi malaria at early patency on day 4 p.i., when parasitized erythrocytes begin to appear in peripheral blood. Using gene expression microarrays, 23 genes were identified to be induced in the liver by >10-fold at p<0.01. More than one third were genes involved in erythropoiesis, as e.g. Kel, Rhag, Ahsp, Ermap, Slc4a1, Cldn13 Gata1, and Gfi1b. Another group of >10-fold expressed genes contain genes involved in natural cytotoxicity, as those encoding the killer cell lectin-like like receptors Klrb1a, Klrc3, Klrd1, Ncr1 and the granzyme B encoding Gzmb. In addition, there were identified a series of genes involved in the control of cell cycle and mitosis, as Ccnb1, Cdc25c, Ckap2l expressed by >10-fold only in vaccination-protected mice, and 22 genes being at least 100% higher expressed in vaccination-protected mice than the corresponding genes significantly expressed in non-vaccinated mice. Furthermore, distinct lincRNA species were changed by >3-fold in livers of vaccination-protected mice, whereas lethal malaria induced different lincRNAs. Our data suggest that protective vaccination accelerates extramedullary erythropoiesis, generation of liver-resident cytotoxic cells, and regeneration from malaria-induced injuries in the liver at early patency, which may be critical for final survival of otherwise lethal blood-stage malaria of P. chabaudi. Mice: Balb/c mice breeded under specified pathogen-free conditions were delivered from central animal facilities of the University of Düsseldorf. The experiments were performed only with female mice aged 10-12 weeks. They were housed in plastic cages, received a standard diet (Woehrlin, Bad Salzuflen, Germany) and water ad libitum. This study was carried out in strict accordance with the German law on animal protection. The keeping of mice as well as the experimental protocol of the study were officially approved by the State-controlled Committee on the Ethics of Animal Experiments of the State Nordrhein-Westfalen, Germany, and were regularly controlled, without being previously announced, by the local authorities. All efforts were undertaken to minimize suffering of mice. P. chabaudi malaria infection: Blood-stage infections of P. chabaudi were kept in outbred mice under sterile conditions by weekly passages of infected blood. A non-clonal line of P. chabaudi is used in our laboratory since 1982, which resembles to P. chabaudi chabaudi. Challenge of Balb/c mice with 10^6 P. chabaudi-infected erythrocytes, Protective vaccination: As a vaccine, host cell plasma membranes were used, which were isolated in the form of ghosts from P. chabaudi-parasitized erythrocytes Approximately 10^6 ghosts were suspended in 100 µl Freund’s complete adjuvant (FCA) and subcutaneously injected on week 3 and week 1 before infecting with P. chabaudi-parasitized erythrocytes. Control mice were treated in parallel only FCA.

Project description:BACKGROUND:Vaccination induces survival of otherwise lethal blood-stage infections of the experimental malaria Plasmodium chabaudi. Blood-stage malaria induces extramedullary erythropoiesis in the liver. This study investigates how vaccination affects the course of malaria-induced expression of erythrocytic genes in the liver. METHODS:Female Balb/c mice were vaccinated at week 3 and week 1 before challenging with 106 P. chabaudi-parasitized erythrocytes. The non-infectious vaccine consisted of erythrocyte ghosts isolated from P. chabaudi-infected erythrocytes. Gene expression microarrays and quantitative real-time PCR were used to compare mRNA expression of different erythrocytic genes in the liver of vaccination-protected and non-protected mice during infections on days 0, 1, 4, 8, and 11 p.i. RESULTS:Global transcriptomics analyses reveal vaccination-induced modifications of malaria-induced increases in hepatic gene expression on days 4 and 11 p.i. On these days, vaccination also alters hepatic expression of the erythropoiesis-involved genes Ermap, Kel, Rhd, Rhag, Slc4a1, Gypa, Add2, Ank1, Epb4.1, Epb4.2, Epb4.9, Spta1, Sptb, Tmod1, Ahsp, Acyp1, Gata1, Gfi1b, Tal1, Klf1, Epor, and Cldn13. In vaccination-protected mice, expression of these genes, except Epb4.1, is significantly higher on day 4 p.i. than in un-protected non-vaccinated mice, reaches maximal expression at peak parasitaemia on day 8 p.i., and is slowed down or even decreased towards the end of crisis phase on day 11 p.i.. After day 1 p.i., Epor expression takes about the same course as that of the other erythroid genes. Hepatic expression of Epo, however, is delayed in both vaccinated and non-vaccinated mice for the first 4 days p.i. and is maximal at significantly higher levels in vaccinated mice on day 8 p.i., before declining towards the end of crisis phase on day 11 p.i. CONCLUSION:The present data indicate that vaccination accelerates malaria-induced erythroblastosis in the liver for 1-2 days. This may contribute to earlier replenishment of peripheral red blood cells by liver-derived reticulocytes, which may favour final survival of otherwise lethal blood-stage malaria, since reticulocytes are not preferred as host cells by P. chabaudi.

Project description:Authorization of the Matrix-M-adjuvanted R21 vaccine by three countries and its subsequent endorsement by the World Health Organization (WHO) for malaria prevention in children is a milestone in the fight against malaria. Yet, to meet the unprecedented demand for malarial vaccines, there is a pressing need for additional adjuvants that induce robust and durable vaccine-induced immunity. Here, we performed a comparative assessment of three clinically relevant adjuvants (an alum formulation of the TLR7/8 agonist 3M-052 (3M-052+Alum), the TLR4 agonist GLA-LSQ (GLA in liposome QS-21 formulation), and Matrix-M, the currently approved adjuvant for R21) for their capacity to induce durable immune responses to the R21 malaria vaccine in non-human primates. Immunization of macaques with R21 adjuvanted with 3M-052+Alum on a 0, 8, and 24-week schedule elicited anti-circumsporozoite antibody responses comparable in magnitude to the R21/Matrix-M vaccine and persisted up to 72 weeks with a half-life of 337 (264 – 459) days. A booster dose at 72 weeks induced an antigen-specific recall response, similar to the R21/Matrix-M vaccination. In contrast, R21/GLA-LSQ immunization induced a considerably lower and short-lived response. Consistent with the durability of serum antibody responses, Matrix-M and 3M-052+Alum induced long-lived plasma cells in the bone marrow and other tissues, including the spleen, but GLA-LSQ stimulated only short-lived plasmablasts. Finally, we show distinct innate immune signatures early after vaccination with these adjuvants. While 3M-052+Alum stimulated potent and persistent antiviral transcriptional and cytokine signatures after primary and booster immunizations, Matrix-M induced an enhanced expression of interferon- and Th2-related signatures more highly after the booster vaccination. Collectively, these findings provide a comparative database on the immune responses of three clinically relevant adjuvants with R21 and highlight the promise of 3M-052+Alum as an additional adjuvant for the R21 malaria vaccine.

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Vaccination accelerates hepatic erythropoiesis induced by blood-stage malaria

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