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      Blood-stage immunity to Plasmodium chabaudi malaria following chemoprophylaxis and sporozoite immunization

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          Abstract

          Protection against malaria in humans can be achieved by repeated exposure to infected mosquito bites during prophylactic chloroquine treatment (chemoprophylaxis and sporozoites (CPS)). We established a new mouse model of CPS immunization to investigate the stage and strain-specificity of malaria immunity. Immunization with Plasmodium chabaudi by mosquito bite under chloroquine cover does not generate pre-erythrocytic immunity, which is acquired only after immunization with high sporozoite doses. Instead, CPS immunization by bite elicits long-lived protection against blood-stage parasites. Blood-stage immunity is effective against a virulent, genetically distinct strain of P. chabaudi. Importantly, if exposure to blood-stage parasitemia is extended, blood-stage parasites induce cross-stage immunity targeting pre-erythrocytic stages. We therefore show that CPS immunization can induce robust, long-lived heterologous blood-stage immunity, in addition to protection against pre-erythrocytic parasites following high dose sporozoite immunization. Cross-stage immunity elicited by blood-stage parasites may further enhance efficacy of this immunization regimen.

          DOI: http://dx.doi.org/10.7554/eLife.05165.001

          eLife digest

          Malaria is a life-threatening infectious disease in humans that is caused by a single-celled parasite called Plasmodium. The parasite is carried between people by mosquitos; when an infected mosquito bites a human, the parasite is injected into the bloodstream with the mosquito's saliva. Plasmodium first infects liver cells but then re-enters the bloodstream, where it infects red blood cells leading to symptoms of disease. If another mosquito bites the infected individual at this so-called ‘blood-stage’, the parasite can be passed to this mosquito and the cycle of transmission continues.

          Currently there are no vaccines available that can effectively protect against malaria. Although an experimental vaccine containing a weakened form of the parasite can protect against the liver-stage parasites, it fails to prevent the parasite from multiplying in the red blood cells. Therefore, the individuals remain susceptible to severe malaria.

          Recently, researchers have developed a new strategy for immunization that provides exposure to both liver-stage and blood-stage parasites. Human volunteers taking an anti-malarial drug were deliberately exposed to mosquitos carrying the parasite on three separate occasions. Although the volunteers were infected with the parasite, the anti-malarial drug killed the parasites inside the red blood cells. After the end of the drug treatment, the volunteers were exposed to mosquitos carrying the parasite and they were still protected from infection. These results are promising, but it is not clear if the volunteers have acquired immunity to liver-stage or blood-stage parasites, or even both.

          To answer this important question, Nahrendorf et al. developed a similar immunization strategy in mice. Just like the human volunteers, the mice were treated with an anti-malarial drug and exposed to mosquitos carrying Plasmodium on three separate occasions. Although the immunizations did not protect the mice against early infection in the liver, they did provide long-term protection against parasites multiplying in the red-blood cells.

          The immunity generated by this immunization strategy also protected the mice against another strain of Plasmodium, different to the one used in the immunizations. The experiments also show that prolonged exposure to the blood-stage parasites can even lead to immunity against the liver-stage parasites.

          Nahrendorf et al.'s findings show that this immunization strategy can protect individuals against both the liver-stage and blood-stage parasites. The next challenges are to find out how the immunity generated by one stage of infection can protect against the other stages, and to discover which molecules on the parasite the immune system targets.

          DOI: http://dx.doi.org/10.7554/eLife.05165.002

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          Most cited references54

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          Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.

          A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
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            Protection against a malaria challenge by sporozoite inoculation.

            An effective vaccine for malaria is urgently needed. Naturally acquired immunity to malaria develops slowly, and induction of protection in humans can be achieved artificially by the inoculation of radiation-attenuated sporozoites by means of more than 1000 infective mosquito bites. We exposed 15 healthy volunteers--with 10 assigned to a vaccine group and 5 assigned to a control group--to bites of mosquitoes once a month for 3 months while they were receiving a prophylactic regimen of chloroquine. The vaccine group was exposed to mosquitoes that were infected with Plasmodium falciparum, and the control group was exposed to mosquitoes that were not infected with the malaria parasite. One month after the discontinuation of chloroquine, protection was assessed by homologous challenge with five mosquitoes infected with P. falciparum. We assessed humoral and cellular responses before vaccination and before the challenge to investigate correlates of protection. All 10 subjects in the vaccine group were protected against a malaria challenge with the infected mosquitoes. In contrast, patent parasitemia (i.e., parasites found in the blood on microscopical examination) developed in all five control subjects. Adverse events were mainly reported by vaccinees after the first immunization and by control subjects after the challenge; no serious adverse events occurred. In this model, we identified the induction of parasite-specific pluripotent effector memory T cells producing interferon-gamma, tumor necrosis factor alpha, and interleukin-2 as a promising immunologic marker of protection. Protection against a homologous malaria challenge can be induced by the inoculation of intact sporozoites. (ClinicalTrials.gov number, NCT00442377.) 2009 Massachusetts Medical Society
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              Protective immunity produced by the injection of x-irradiated sporozoites of plasmodium berghei.

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                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                2050-084X
                25 February 2015
                2015
                : 4
                : e05165
                Affiliations
                [1 ]deptDivision of Parasitology , MRC National Institute for Medical Research , London, United Kingdom
                [2 ]deptDepartment of Medical Microbiology , Radboud University Medical Centre , Nijmegen, Netherlands
                Walter Reed Army Institute of Research , United States
                Walter Reed Army Institute of Research , United States
                Author notes
                [* ]For correspondence: Wiebke.Nahrendorf@ 123456ed.ac.uk (WN);
                [†]

                Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.

                [‡]

                Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom.

                [§]

                Mill Hill Laboratories, Francis Crick Institute, London, United Kingdom.

                Article
                05165
                10.7554/eLife.05165
                4371380
                25714922
                62194a6f-bd28-42b0-9a30-fafabe130867
                © 2015, Nahrendorf et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 14 October 2014
                : 23 February 2015
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000275, Leverhulme Trust;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council (MRC);
                Award ID: U117584248
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Immunology
                Microbiology and Infectious Disease
                Custom metadata
                2.0
                A novel mouse model of immunization against Plasmodium chabaudi involving infectious mosquito bites and drug-treatment elicits protection against blood-stage malaria parasites, and shows that protection is not necessarily life cycle stage-specific.

                Life sciences
                malaria,vaccine,protection,sporozoites,cross-stage,mouse
                Life sciences
                malaria, vaccine, protection, sporozoites, cross-stage, mouse

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