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The evolutionary consequences of blood-stage vaccination on the rodent malaria Plasmodium chabaudi.

ABSTRACT: Malaria vaccine developers are concerned that antigenic escape will erode vaccine efficacy. Evolutionary theorists have raised the possibility that some types of vaccine could also create conditions favoring the evolution of more virulent pathogens. Such evolution would put unvaccinated people at greater risk of severe disease. Here we test the impact of vaccination with a single highly purified antigen on the malaria parasite Plasmodium chabaudi evolving in laboratory mice. The antigen we used, AMA-1, is a component of several candidate malaria vaccines currently in various stages of trials in humans. We first found that a more virulent clone was less readily controlled by AMA-1-induced immunity than its less virulent progenitor. Replicated parasites were then serially passaged through control or AMA-1 vaccinated mice and evaluated after 10 and 21 rounds of selection. We found no evidence of evolution at the ama-1 locus. Instead, virulence evolved; AMA-1-selected parasites induced greater anemia in naïve mice than both control and ancestral parasites. Our data suggest that recombinant blood stage malaria vaccines can drive the evolution of more virulent malaria parasites.

SUBMITTER: Barclay VC

PROVIDER: S-EPMC3409122 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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The evolutionary consequences of blood-stage vaccination on the rodent malaria Plasmodium chabaudi.

Barclay Victoria C VC Sim Derek D Chan Brian H K BH Nell Lucas A LA Rabaa Maia A MA Bell Andrew S AS Anders Robin F RF Read Andrew F AF

PLoS biology 20120731 7

Malaria vaccine developers are concerned that antigenic escape will erode vaccine efficacy. Evolutionary theorists have raised the possibility that some types of vaccine could also create conditions favoring the evolution of more virulent pathogens. Such evolution would put unvaccinated people at greater risk of severe disease. Here we test the impact of vaccination with a single highly purified antigen on the malaria parasite Plasmodium chabaudi evolving in laboratory mice. The antigen we used, ...[more]

PMID: 22870063

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Project description: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.

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.

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The evolutionary consequences of blood-stage vaccination on the rodent malaria Plasmodium chabaudi.

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The evolutionary consequences of blood-stage vaccination on the rodent malaria Plasmodium chabaudi.

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