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      Schistosoma mansoni infection suppresses the growth of Plasmodium yoelii parasites in the liver and reduces gametocyte infectivity to mosquitoes

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          Abstract

          Malaria and schistosomiasis are major parasitic diseases causing morbidity and mortality in the tropics. Epidemiological surveys have revealed coinfection rates of up to 30% among children in Sub-Saharan Africa. To investigate the impact of coinfection of these two parasites on disease epidemiology and pathology, we carried out coinfection studies using Plasmodium yoelii and Schistosoma mansoni in mice. Malaria parasite growth in the liver following sporozoite inoculation is significantly inhibited in mice infected with S. mansoni, so that when low numbers of sporozoites are inoculated, there is a large reduction in the percentage of mice that go on to develop blood stage malaria. Furthermore, gametocyte infectivity is much reduced in mice with S. mansoni infections. These results have profound implications for understanding the interactions between Plasmodium and Schistosoma species, and have implications for the control of malaria in schistosome endemic areas.

          Author summary

          Malaria and schistosomiasis are parasitic infectious diseases that cause severe morbidity and mortality in the tropics. Chronic schistosomiasis causes malnutrition and impaired intellectual development to children while malaria can cause fatal acute infections. Since coinfection of these two parasites is common in the tropics, many studies of both epidemiology and coinfection in animal models have been performed in order to reveal interactions between them. Previous animal studies on the interactions between Plasmodium and Schistosoma parasites have focused on the blood stage pathology of the malaria infection, and have consistently shown that parasitaemia can be enhanced in the presence of the helminth. In contrast, we focused on liver immunopathology in mice during coinfection between with Schistosoma and Plasmodium. We show that S. mansoni infection inhibits Plasmodium parasite growth in the liver resulting in a large reduction in the percentage of mice that go on to develop blood stage malaria following inoculation of low numbers of sporozoites. We also demonstrate that gametocyte infectivity is much reduced in mice with S. mansoni infections. Our results imply that S. mansoni infection can reduce malaria transmission both from mosquitoes to mice, and from mice to mosquitoes.

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          Most cited references44

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          The major component in schistosome eggs responsible for conditioning dendritic cells for Th2 polarization is a T2 ribonuclease (omega-1)

          Schistosoma mansoni eggs contain factors that trigger potent Th2 responses in vivo and condition mouse dendritic cells (DCs) to promote Th2 lymphocyte differentiation. Using an in vitro bystander polarization assay as the readout, we purified and identified the major Th2-inducing component from soluble egg extract (SEA) as the secreted T2 ribonuclease, omega-1. The Th2-promoting activity of omega-1 was found to be sensitive to ribonuclease inhibition and did not require MyD88/TRIF signaling in DCs. In common with unfractioned SEA, the purified native protein suppresses lipopolysaccharide-induced DC activation, but unlike SEA, it fails to trigger interleukin 4 production from basophils. Importantly, omega-1–exposed DCs displayed pronounced cytoskeletal changes and exhibited decreased antigen-dependent conjugate formation with CD4+ T cells. Based on this evidence, we hypothesize that S. mansoni omega-1 acts by limiting the interaction of DCs with CD4+ T lymphocytes, thereby lowering the strength of the activation signal delivered.
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            Superior antimalarial immunity after vaccination with late liver stage-arresting genetically attenuated parasites.

            While subunit vaccines have shown partial efficacy in clinical trials, radiation-attenuated sporozoites (RAS) remain the "gold standard" for sterilizing protection against Plasmodium infection in human vaccinees. The variability in immunogenicity and replication introduced by the extensive, random DNA damage necessary to generate RAS could be overcome by genetically attenuated parasites (GAP) designed via gene deletion to arrest at defined points during liver-stage development. Here, we demonstrate the principle that late liver stage-arresting GAP induce larger and broader CD8 T cell responses that provide superior protection in inbred and outbred mice compared to RAS or early-arresting GAP immunizations. Late liver stage-arresting GAP also engender high levels of cross-stage and cross-species protection and complete protection when administered by translationally relevant intradermal or subcutaneous routes. Collectively, our results underscore the potential utility of late liver stage-arresting GAP as broadly protective next-generation live-attenuated malaria vaccines and support their potential as a powerful model for identifying antigens to generate cross-stage protection. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Interferon-mediated innate immune responses against malaria parasite liver stages.

              Mosquito-transmitted malaria parasites infect hepatocytes and asymptomatically replicate as liver stages. Using RNA sequencing, we show that a rodent malaria liver-stage infection stimulates a robust innate immune response including type I interferon (IFN) and IFNγ pathways. Liver-stage infection is suppressed by these infection-engendered innate responses. This suppression was abrogated in mice deficient in IFNγ, the type I IFN α/β receptor (IFNAR), and interferon regulatory factor 3. Natural killer and CD49b(+)CD3(+) natural killer T (NKT) cells increased in the liver after a primary infection, and CD1d-restricted NKT cells, which secrete IFNγ, were critical in reducing liver-stage burden of a secondary infection. Lack of IFNAR signaling abrogated the increase in NKT cell numbers in the liver, showing a link between type I IFN signaling, cell recruitment, and subsequent parasite elimination. Our findings demonstrate innate immune sensing of malaria parasite liver-stage infection and that the ensuing innate responses can eliminate the parasite.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing – original draft
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: Methodology
                Role: Methodology
                Role: Resources
                Role: Conceptualization
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                26 January 2018
                January 2018
                : 12
                : 1
                : e0006197
                Affiliations
                [1 ] Leading Program, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
                [2 ] Department of Parasitology, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan
                [3 ] The Joint Usage/Research Center on Tropical Disease, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan
                [4 ] Pathology Unit, Department of Pathology, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan
                [5 ] Laboratory for Cytokine Regulation, Research Center for Integrative Medical Science (IMS), RIKEN Yokohama Institute, Yokohama, Japan
                [6 ] Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo University of Science, Noda, Japan
                [7 ] Malaria Unit, Department of Pathology, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan
                Queen's University Belfast, UNITED KINGDOM
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-8201-3061
                Article
                PNTD-D-17-01599
                10.1371/journal.pntd.0006197
                5802944
                29373600
                4c4968be-5225-4dea-861b-4c3ab6672296
                © 2018 Moriyasu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 October 2017
                : 28 December 2017
                Page count
                Figures: 7, Tables: 1, Pages: 17
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: JP25870525, JP24255009 and JP16K21233
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: JP17H01684 and S2509
                Award Recipient :
                Funded by: A Royal Society Bilateral Grant for Co-operative Research
                Award Recipient :
                Funded by: Sasakawa Foundation Butterfield Award
                Award Recipient :
                Funded by: Global Center of Excellence (GCOE) Program at Nagasaki University
                Award Recipient :
                This work was supported by the Japan Society for the Promotion of Science (JSPS)( http://www.jsps.go.jp/english/) of project numbers JP25870525, JP24255009 and JP16K21233 to RC, JP17H01684 and S2509 to SH; A Royal Society Bilateral Grant for Co-operative Research https://royalsociety.org/grants-schemes-awards/grants/) to RC; a Sasakawa Foundation Butterfield Award ( http://www.gbsf.org.uk/butterfieldawards/) to RC; the Global Center of Excellence (GCOE) Program at Nagasaki University ( http://www.tm.nagasaki-u.ac.jp/gcoe/) to SH. TM was supported by a PhD scholarship by the Leading Program, Graduate School of Biomedical Sciences, Nagasaki University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Eukaryota
                Protozoans
                Parasitic Protozoans
                Malarial Parasites
                Medicine and Health Sciences
                Parasitic Diseases
                Medicine and Health Sciences
                Parasitic Diseases
                Malaria
                Medicine and Health Sciences
                Tropical Diseases
                Malaria
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Invertebrates
                Helminths
                Schistosoma
                Schistosoma Mansoni
                Biology and Life Sciences
                Organisms
                Eukaryota
                Protozoans
                Parasitic Protozoans
                Malarial Parasites
                Plasmodium Yoelii
                Research and Analysis Methods
                Experimental Organism Systems
                Model Organisms
                Mouse Models
                Research and Analysis Methods
                Model Organisms
                Mouse Models
                Research and Analysis Methods
                Experimental Organism Systems
                Animal Models
                Mouse Models
                Biology and Life Sciences
                Parasitology
                Parasite Groups
                Apicomplexa
                Plasmodium
                Medicine and Health Sciences
                Infectious Diseases
                Disease Vectors
                Insect Vectors
                Mosquitoes
                Biology and Life Sciences
                Species Interactions
                Disease Vectors
                Insect Vectors
                Mosquitoes
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Invertebrates
                Arthropoda
                Insects
                Mosquitoes
                Custom metadata
                vor-update-to-uncorrected-proof
                2018-02-07
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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