The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
Stephen L. Hoffman - One of the best experts on this subject based on the ideXlab platform.
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determining liver Stage parasite burden by real time quantitative pcr as a method for evaluating pre Erythrocytic malaria vaccine efficacy
Molecular and Biochemical Parasitology, 2001Co-Authors: Adam A Witney, Denise L. Doolan, Stephen L. Hoffman, Robert M Anthony, Walter R Weiss, Daniel J CarucciAbstract:The detection and quantitation of blood Stage parasitaemia is typically used as a surrogate endpoint for estimating the efficacy of vaccines targeted against the hepatic Stage, as well as the Erythrocytic Stage, of the parasite. However, this does not provide an adequate means of evaluating the efficacy of vaccines, which may be only partially effective at the liver-Stage. This is a particular concern for effective evaluation of immune enhancement strategies for candidate pre-Erythrocytic Stage vaccines. Here, we have developed and validated a method for detecting and quantitating liver Stage parasites, using the TaqMan® fluorescent real-time quantitative PCR system (PE Applied Biosystems). This method uses TaqMan® primers designed to the Plasmodiumyoelii 18S rRNA gene and rodent GAPDH to amplify products from infected mouse liver cDNA. The technique is highly reproducible as demonstrated with plasmid controls and capable of efficiently quantitating liver-Stage parasite burden following a range of sporozoite challenge doses in strains of mice, which differ in their susceptibility to sporozoite infection. We have further demonstrated the capacity of this technique to evaluate the efficacy of a range of pre-Erythrocytic Stage vaccines. Our data establish this quantitative real-time PCR assay to be a fast and reproducible way of accurately assessing liver Stage parasite burden and vaccine efficacy in rodent malaria models.
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Pre–Erythrocytic–Stage immune effector mechanisms in Plasmodium spp. infections
Philosophical transactions of the Royal Society of London. Series B Biological sciences, 1997Co-Authors: Denise L. Doolan, Stephen L. HoffmanAbstract:The potent protective immunity against malaria induced by immunization of mice and humans with radiation–attenuated Plasmodium spp. sporozoites is thought to be mediated primarily by T–cell responses directed against infected hepatocytes. This has led to considerable efforts to develop subunit vaccines that duplicate this protective immunity, but a universally effective vaccine is still not available and in vitro correlates of protective immunity have not been established. Contributing to this delay has been a lack of understanding of the mechanisms responsible for the protection. There are now data indicating that CD8+ T cells, CD4+ T cells, cytokines, and nitric oxide can all mediate the elimination of infected hepatocytes in vitro and in vivo . By dissecting the protection induced by immunization with irradiated sporozoite, DNA and synthetic peptide–adjuvant vaccines, we have demonstrated that different T–cell–dependent immune responses mediate protective immunity in the same inbred strain of mouse, depending on the method of immunization. Furthermore, the mechanism of protection induced by a single method of immunization may vary among different strains of mice. These data have important implications for the development of pre–Erythrocytic–Stage vaccines designed to protect a heterogeneous human population, and of assays that predict protective immunity.
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pre Erythrocytic Stage immune effector mechanisms in plasmodium spp infections
Philosophical Transactions of the Royal Society B, 1997Co-Authors: Denise L. Doolan, Stephen L. HoffmanAbstract:The potent protective immunity against malaria induced by immunization of mice and humans with radiation–attenuated Plasmodium spp. sporozoites is thought to be mediated primarily by T–cell responses directed against infected hepatocytes. This has led to considerable efforts to develop subunit vaccines that duplicate this protective immunity, but a universally effective vaccine is still not available and in vitro correlates of protective immunity have not been established. Contributing to this delay has been a lack of understanding of the mechanisms responsible for the protection. There are now data indicating that CD8+ T cells, CD4+ T cells, cytokines, and nitric oxide can all mediate the elimination of infected hepatocytes in vitro and in vivo . By dissecting the protection induced by immunization with irradiated sporozoite, DNA and synthetic peptide–adjuvant vaccines, we have demonstrated that different T–cell–dependent immune responses mediate protective immunity in the same inbred strain of mouse, depending on the method of immunization. Furthermore, the mechanism of protection induced by a single method of immunization may vary among different strains of mice. These data have important implications for the development of pre–Erythrocytic–Stage vaccines designed to protect a heterogeneous human population, and of assays that predict protective immunity.
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protective efficacy against malaria of a combination sporozoite and Erythrocytic Stage vaccine
Immunology Letters, 1996Co-Authors: Ruobing Wang, Carole A Long, Yupin Charoenvit, Thomas M Daly, Giampietro Corradin, Stephen L. HoffmanAbstract:Most malariologists believe that optimal malaria vaccines will induce protective immune responses against different Stages of the parasite's life cycle. A multiple antigen peptide (MAP) vaccine based on the Plasmodium yoelii circumsporozoite protein (PyCSP) protects mice against sporozoite challenge by inducing antibodies that prevent sporozoites from invading hepatocytes. A purified recombinant protein vaccine based on the P. yoelii merozoite surface protein-1 (PyMSP-1) protects mice against challenge with infected erythrocytes, presumably by inducing antibodies against the Erythrocytic Stage of the parasite. We now report studies designed to determine if the PyMSP-1 vaccine protects against challenge with sporozoites, the Stage encountered in the field, and if immunization with a combination of the PyCSP and PyMSP-1 vaccines provides additive or synergistic protection against sporozoite challenge. In two experiments, using TiterMax or Ribi R-700 as adjuvant, 3 of 19 mice immunized with the PyMSP-1 vaccine were completely protected against sporozoite challenge. The remaining mice had significantly delayed onset and lower levels of peak parasitemia than did control mice (11.1 +/- 2.8% vs. 36.7 +/- 1.6% in experiment #2, P < 0.01). Immunization with the combination vaccine reduced by approximately 50% the level of antibodies induced to PyCSP and PyMSP-1, as compared to that induced by the individual components. However, in two experiments, there was evidence of additive protection. Six of 19 (31.6%) immunized with the PyCSP vaccine, 3 of 19 (15.8%) immunized with the PyMSP-1 vaccine, and 10 of 19 (52.6%) immunized with the combination were completely protected against sporozoit challenge. This modest increase in protection in the combination group may be a reflection of additive anti-PyCSP and anti-PyMSP-1 immunity, since mice in the combination group had diminished levels of antibodies to each components. These studies indicate that considerable work may be required to optimize the construction, delivery, and assessment of multi-Stage malaria vaccines.
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Plasmodium yoelii: 17-kDa hepatic and Erythrocytic Stage protein is the target of an inhibitory monoclonal antibody.
Experimental parasitology, 1995Co-Authors: Yupin Charoenvit, Masamichi Aikawa, Sylvie Mellouk, Martha Sedegah, Tetsuhiko Toyoshima, M. F. Leef, P. De La Vega, Richard L. Beaudoin, V. Fallarme, Stephen L. HoffmanAbstract:Abstract Infected hepatocytes are important targets for malaria vaccines. To identify Plasmodium yoelii proteins expressed in infected hepatocytes, we immunized BALB/c ByJ mice with P. yoelii liver Stage schizonts and produced a panel of monoclonal antibodies (Mabs). An IgG1 Mab, navy yoelii liver Stage 3 (NYLS3), had the strongest reactivity against liver Stage parasites and was selected for further characterization. The Mab does not recognize P. yoelii sporozoites, but recognizes liver Stages parasites within 6 hr of invasion of mouse hepatocytes and throughout the hepatic and asexual Erythrocytic Stages of the parasite life cycle as determined by the immunofluorescent antibody test. This Mab is species-specific, and it reacts with liver Stages of P. yoelii but does not react with liver Stages of other Plasmodium species. The protein recognized by this Mab is present on the parasitophorous vacuole membrane of infected hepatocytes and erythrocytes as demonstrated by immunoelectron microscopy and has a relative molecular weight of 17 kDa as demonstrated by immunoblot of an extract of infected erythrocytes. It is therefore designated P. yoelii hepatic and Erythrocytic Stage protein, 17 kDa or PyHEP17. When added to primary cultures of mouse hepatocytes 24 hr after inoculation with P. yoelii sporozoites, when all sporozoites have invaded hepatocytes, NYLS3 eliminates up to 98% of liver-Stage parasites. Intravenous injection of NYLS3 into mice delays the onset and reduces the density of blood-Stage parasitemia after sporozoite or blood-Stage challenge. The P. falciparum and P. vivax homologs of PyHEP17 may therefore be important targets for vaccines designed to attack the hepatic and Erythrocytic Stages of the parasite life cycle.
Stefan H I Kappe - One of the best experts on this subject based on the ideXlab platform.
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blood Stage malaria disrupts humoral immunity to the pre Erythrocytic Stage circumsporozoite protein
Cell Reports, 2016Co-Authors: Gladys J Keitany, Akshay T Krishnamurty, Brian D Hondowicz, William O Hahn, Nicholas Dambrauskas, Noah D Sather, Ashley M Vaughan, Stefan H I Kappe, Marion PepperAbstract:Many current malaria vaccines target the pre-Erythrocytic Stage of infection in the liver. However, in malaria-endemic regions, increased blood Stage exposure is associated with decreased vaccine efficacy, thereby challenging current vaccine efforts. We hypothesized that pre-Erythrocytic humoral immunity is directly disrupted by blood Stage infection. To investigate this possibility, we used Plasmodium-antigen tetramers to analyze B cells after infection with either late liver Stage arresting parasites or wild-type parasites that progress to the blood Stage. Our data demonstrate that immunoglobulin G (IgG) antibodies against the pre-Erythrocytic antigen, circumsporozoite protein (CSP), are generated only in response to the attenuated, but not the wild-type, infection. Further analyses revealed that blood Stage malaria inhibits CSP-specific germinal center B cell differentiation and modulates chemokine expression. This results in aberrant memory formation and the loss of a rapid secondary B cell response. These data highlight how immunization with attenuated parasites may drive optimal immunity to malaria.
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malaria parasite pre Erythrocytic Stage infection gliding and hiding
Cell Host & Microbe, 2008Co-Authors: Ashley M Vaughan, Stefan H I Kappe, Ahmed S I AlyAbstract:In malaria, the red blood cell-infectious form of the Plasmodium parasite causes illness and the possible death of infected hosts. The initial infection in the liver caused by the mosquito-borne sporozoite parasite Stage, however, causes little pathology and no symptoms. Nevertheless, pre-Erythrocytic parasite Stages are attracting passionate research efforts not least because they are the most promising targets for malaria vaccine development. Here, we review how the infectious sporozoite makes its way to the liver and subsequently develops within hepatocytes. We discuss the factors, both parasite and host, involved in the interactions that occur during this "silent" phase of infection.
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differential transcriptome profiling identifies plasmodium genes encoding pre Erythrocytic Stage specific proteins
Molecular Microbiology, 2004Co-Authors: Karine Kaiser, Kai Matuschewski, Nelly Camargo, Jessica Ross, Stefan H I KappeAbstract:Summary Invasive sporozoite and merozoite Stages of malaria parasites that infect mammals enter and subsequently reside in hepatocytes and red blood cells respectively. Each invasive Stage may exhibit unique adaptations that allow it to interact with and survive in its distinct host cell environment, and these adaptations are likely to be controlled by differential gene expression. We used suppression subtractive hybridization (SSH) of Plasmodium yoelii salivary gland sporozoites versus merozoites to identify Stage-specific pre-Erythrocytic transcripts. Sequencing of the SSH library and matching the cDNA sequences to the P. yoelii genome yielded 25 redundantly tagged genes including the only two previously characterized sporozoite-specific genes encoding the circumsporozoite protein (CSP) and thrombospondin-related anonymous protein (TRAP). Twelve novel genes encode predicted proteins with signal peptides, indicating that they enter the secretory pathway of the sporozoite. We show that one novel protein bearing a thrombospondin type 1 repeat (TSR) exhibits an expression pattern that suggests localization in the sporozoite secretory rhoptry organelles. In addition, we identified a group of four genes encoding putative low-molecular-mass proteins. Two proteins in this group exhibit an expression pattern similar to TRAP, and thus possibly localize in the sporozoite secretory micronemes. Proteins encoded by the differentially expressed genes identified here probably mediate specific interactions of the sporozoite with the mosquito vector salivary glands or the mammalian host hepatocyte and are not used during merozoite–red blood cell interactions.
Denise L. Doolan - One of the best experts on this subject based on the ideXlab platform.
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Immune response to pre-Erythrocytic Stages of malaria parasites
Current molecular medicine, 2006Co-Authors: Denise L. Doolan, Nuria Martinez-alierAbstract:Immunization with radiation-attenuated Plasmodium spp. sporozoites induces sterile protective immunity against parasite challenge. This immunity is targeted primarily against the intrahepatic parasite and appears to be sustained long term even in the absence of sporozoite exposure. It is mediated by multifactorial mechanisms, including T cells directed against parasite antigens expressed in the liver Stage of the parasite life cycle and antibodies directed against sporozoite surface proteins. In rodent models, CD8+ T cells have been implicated as the principal effector cells, and IFN-gamma as a critical effector molecule. IL-4 secreting CD4+ T cells are required for induction of the CD8+ T cell responses, and Th1 CD4+ T cells provide help for optimal CD8+ T cell effector activity. Components of the innate immune system, including gamma-delta T cells, natural killer cells and natural killer T cells, also play a role. The precise nature of pre-Erythrocytic Stage immunity in humans, including the contribution of these immune responses to the age-dependent immunity naturally acquired by residents of malaria endemic areas, is still poorly defined. The importance of immune effector targets at the pre-Erythrocytic Stage of the parasite life cycle is highlighted by the fact that infection-blocking immunity in humans rarely, if ever, occurs under natural conditions. Herein, we review our current understanding of the molecular and cellular aspects of pre-Erythrocytic Stage immunity.
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determining liver Stage parasite burden by real time quantitative pcr as a method for evaluating pre Erythrocytic malaria vaccine efficacy
Molecular and Biochemical Parasitology, 2001Co-Authors: Adam A Witney, Denise L. Doolan, Stephen L. Hoffman, Robert M Anthony, Walter R Weiss, Daniel J CarucciAbstract:The detection and quantitation of blood Stage parasitaemia is typically used as a surrogate endpoint for estimating the efficacy of vaccines targeted against the hepatic Stage, as well as the Erythrocytic Stage, of the parasite. However, this does not provide an adequate means of evaluating the efficacy of vaccines, which may be only partially effective at the liver-Stage. This is a particular concern for effective evaluation of immune enhancement strategies for candidate pre-Erythrocytic Stage vaccines. Here, we have developed and validated a method for detecting and quantitating liver Stage parasites, using the TaqMan® fluorescent real-time quantitative PCR system (PE Applied Biosystems). This method uses TaqMan® primers designed to the Plasmodiumyoelii 18S rRNA gene and rodent GAPDH to amplify products from infected mouse liver cDNA. The technique is highly reproducible as demonstrated with plasmid controls and capable of efficiently quantitating liver-Stage parasite burden following a range of sporozoite challenge doses in strains of mice, which differ in their susceptibility to sporozoite infection. We have further demonstrated the capacity of this technique to evaluate the efficacy of a range of pre-Erythrocytic Stage vaccines. Our data establish this quantitative real-time PCR assay to be a fast and reproducible way of accurately assessing liver Stage parasite burden and vaccine efficacy in rodent malaria models.
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in vitro expression and in vivo immunogenicity of plasmodium falciparum pre Erythrocytic Stage dna vaccines
International Journal of Molecular Medicine, 1998Co-Authors: Richard C Hedstrom, Malcolm J. Gardner, Denise L. Doolan, Yupin Charoenvit, Martha Sedegah, R Wang, Anita Kumar, John B Sacci, Joao C Aguiar, John A TineAbstract:DNA vaccine plasmids were constructed that encoded four pre-Erythrocytic antigens from the human malaria parasite Plasmodium falciparum: circumsporozoite protein (PfCSP); sporozoite surface protein 2 (PfSSP2); carboxyl terminus of liver Stage antigen 1 (PfLSA-1 c-term); and, exported protein 1 (PfExp-1). Antigen expression was evaluated in vitro by immunoblot analysis of tissue culture cells following transient transfection with each plasmid. Clearly detectable levels of expression depended upon, or were markedly enhanced by, fusion of the antigen encoding sequences in-frame with the initiation complex and peptide leader sequence of human tissue plasminogen activator protein. Mice injected with these plasmids produced antigen specific antibody and cytotoxic T lymphocyte responses. However, the magnitudes of the responses were not always predicted by the in vitro expression assay. The results of this study provided the basis for further testing of these plasmids in primates and the formulation of multi-component pre-Erythrocytic DNA vaccines for efficacy testing in human volunteers.
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Pre–Erythrocytic–Stage immune effector mechanisms in Plasmodium spp. infections
Philosophical transactions of the Royal Society of London. Series B Biological sciences, 1997Co-Authors: Denise L. Doolan, Stephen L. HoffmanAbstract:The potent protective immunity against malaria induced by immunization of mice and humans with radiation–attenuated Plasmodium spp. sporozoites is thought to be mediated primarily by T–cell responses directed against infected hepatocytes. This has led to considerable efforts to develop subunit vaccines that duplicate this protective immunity, but a universally effective vaccine is still not available and in vitro correlates of protective immunity have not been established. Contributing to this delay has been a lack of understanding of the mechanisms responsible for the protection. There are now data indicating that CD8+ T cells, CD4+ T cells, cytokines, and nitric oxide can all mediate the elimination of infected hepatocytes in vitro and in vivo . By dissecting the protection induced by immunization with irradiated sporozoite, DNA and synthetic peptide–adjuvant vaccines, we have demonstrated that different T–cell–dependent immune responses mediate protective immunity in the same inbred strain of mouse, depending on the method of immunization. Furthermore, the mechanism of protection induced by a single method of immunization may vary among different strains of mice. These data have important implications for the development of pre–Erythrocytic–Stage vaccines designed to protect a heterogeneous human population, and of assays that predict protective immunity.
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pre Erythrocytic Stage immune effector mechanisms in plasmodium spp infections
Philosophical Transactions of the Royal Society B, 1997Co-Authors: Denise L. Doolan, Stephen L. HoffmanAbstract:The potent protective immunity against malaria induced by immunization of mice and humans with radiation–attenuated Plasmodium spp. sporozoites is thought to be mediated primarily by T–cell responses directed against infected hepatocytes. This has led to considerable efforts to develop subunit vaccines that duplicate this protective immunity, but a universally effective vaccine is still not available and in vitro correlates of protective immunity have not been established. Contributing to this delay has been a lack of understanding of the mechanisms responsible for the protection. There are now data indicating that CD8+ T cells, CD4+ T cells, cytokines, and nitric oxide can all mediate the elimination of infected hepatocytes in vitro and in vivo . By dissecting the protection induced by immunization with irradiated sporozoite, DNA and synthetic peptide–adjuvant vaccines, we have demonstrated that different T–cell–dependent immune responses mediate protective immunity in the same inbred strain of mouse, depending on the method of immunization. Furthermore, the mechanism of protection induced by a single method of immunization may vary among different strains of mice. These data have important implications for the development of pre–Erythrocytic–Stage vaccines designed to protect a heterogeneous human population, and of assays that predict protective immunity.
Malcolm J. Gardner - One of the best experts on this subject based on the ideXlab platform.
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plasmodium apicoplast gln trnagln biosynthesis utilizes a unique gatab amidotransferase essential for Erythrocytic Stage parasites
Journal of Biological Chemistry, 2015Co-Authors: Boniface M Mailu, Malcolm J. Gardner, Jen Arthur, Todd M Nelson, Gowthaman Ramasamy, Karin Fritzwolf, Katja BeckerAbstract:The malaria parasite Plasmodium falciparum apicoplast indirect aminoacylation pathway utilizes a non-discriminating glutamyl-tRNA synthetase to synthesize Glu-tRNAGln and a glutaminyl-tRNA amidotransferase to convert Glu-tRNAGln to Gln-tRNAGln. Here, we show that Plasmodium falciparum and other apicomplexans possess a unique heterodimeric glutamyl-tRNA amidotransferase consisting of GatA and GatB subunits (GatAB). We localized the P. falciparum GatA and GatB subunits to the apicoplast in blood Stage parasites and demonstrated that recombinant GatAB converts Glu-tRNAGln to Gln-tRNAGln in vitro. We demonstrate that the apicoplast GatAB-catalyzed reaction is essential to the parasite blood Stages because we could not delete the Plasmodium berghei gene encoding GatA in blood Stage parasites in vivo. A phylogenetic analysis placed the split between Plasmodium GatB, archaeal GatE, and bacterial GatB prior to the phylogenetic divide between bacteria and archaea. Moreover, Plasmodium GatA also appears to have emerged prior to the bacterial-archaeal phylogenetic divide. Thus, although GatAB is found in Plasmodium, it emerged prior to the phylogenetic separation of archaea and bacteria.
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plasmodium vivax pre Erythrocytic Stage antigen discovery exploiting naturally acquired humoral responses
American Journal of Tropical Medicine and Hygiene, 2012Co-Authors: Douglas M. Molina, Olivia C. Finney, Sócrates Herrera, Philip L. Felgner, Malcolm J. Gardner, Xiaowu Liang, Myriam Arevaloherrera, Ruobing WangAbstract:The development of pre-Erythrocytic Plasmodium vivax vaccines is hindered by the lack of in vitro culture systems or experimental rodent models. To help bypass these roadblocks, we exploited the fact that naturally exposed Fy- individuals who lack the Duffy blood antigen (Fy) receptor are less likely to develop blood-Stage infections; therefore, they preferentially develop immune responses to pre-Erythrocytic-Stage parasites, whereas Fy+ individuals experience both liver- and blood-Stage infections and develop immune responses to both pre-Erythrocytic and Erythrocytic parasites. We screened 60 endemic sera from P. vivax-exposed Fy+ or Fy- donors against a protein microarray containing 91 P. vivax proteins with P. falciparum orthologs that were up-regulated in sporozoites. Antibodies against 10 P. vivax antigens were identified in sera from P. vivax-exposed individuals but not unexposed controls. This technology has promising implications in the discovery of potential vaccine candidates against P. vivax malaria.
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Plasmodium vivax Pre-Erythrocytic–Stage Antigen Discovery: Exploiting Naturally Acquired Humoral Responses
The American journal of tropical medicine and hygiene, 2012Co-Authors: Douglas M. Molina, Olivia C. Finney, Myriam Arévalo-herrera, Sócrates Herrera, Philip L. Felgner, Malcolm J. Gardner, Xiaowu Liang, Ruobing WangAbstract:The development of pre-Erythrocytic Plasmodium vivax vaccines is hindered by the lack of in vitro culture systems or experimental rodent models. To help bypass these roadblocks, we exploited the fact that naturally exposed Fy− individuals who lack the Duffy blood antigen (Fy) receptor are less likely to develop blood-Stage infections; therefore, they preferentially develop immune responses to pre-Erythrocytic–Stage parasites, whereas Fy+ individuals experience both liver- and blood-Stage infections and develop immune responses to both pre-Erythrocytic and Erythrocytic parasites. We screened 60 endemic sera from P. vivax-exposed Fy+ or Fy− donors against a protein microarray containing 91 P. vivax proteins with P. falciparum orthologs that were up-regulated in sporozoites. Antibodies against 10 P. vivax antigens were identified in sera from P. vivax-exposed individuals but not unexposed controls. This technology has promising implications in the discovery of potential vaccine candidates against P. vivax malaria.
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in vitro expression and in vivo immunogenicity of plasmodium falciparum pre Erythrocytic Stage dna vaccines
International Journal of Molecular Medicine, 1998Co-Authors: Richard C Hedstrom, Malcolm J. Gardner, Denise L. Doolan, Yupin Charoenvit, Martha Sedegah, R Wang, Anita Kumar, John B Sacci, Joao C Aguiar, John A TineAbstract:DNA vaccine plasmids were constructed that encoded four pre-Erythrocytic antigens from the human malaria parasite Plasmodium falciparum: circumsporozoite protein (PfCSP); sporozoite surface protein 2 (PfSSP2); carboxyl terminus of liver Stage antigen 1 (PfLSA-1 c-term); and, exported protein 1 (PfExp-1). Antigen expression was evaluated in vitro by immunoblot analysis of tissue culture cells following transient transfection with each plasmid. Clearly detectable levels of expression depended upon, or were markedly enhanced by, fusion of the antigen encoding sequences in-frame with the initiation complex and peptide leader sequence of human tissue plasminogen activator protein. Mice injected with these plasmids produced antigen specific antibody and cytotoxic T lymphocyte responses. However, the magnitudes of the responses were not always predicted by the in vitro expression assay. The results of this study provided the basis for further testing of these plasmids in primates and the formulation of multi-component pre-Erythrocytic DNA vaccines for efficacy testing in human volunteers.
Marjorie Mauduit - One of the best experts on this subject based on the ideXlab platform.
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Dendritic cells and the malaria pre-Erythrocytic Stage.
Immunologic research, 2012Co-Authors: Marjorie Mauduit, Peter See, Kaitian Peng, Laurent Rénia, Florent GinhouxAbstract:Malaria remains one of the main infectious diseases in intertropical regions. The malaria parasite has a complex life cycle in its mammalian host, switching between variable forms as it traverses through different tissues and anatomic locations, either intra- or intercellularly. During its journey, the parasite encounters and interacts with the host immune system, which functions to prevent infections and limit ensuing pathologies. One important component of the host immune system is the dendritic cells (DC) network. DC form a heterogeneous group of pathogen-sensing and antigen-presenting cells that play a crucial role in the initiation of adaptive immunity. Here, we review the known and unknown interactions between the malaria parasites and the DC system, starting from the inoculation of the parasite in the skin up to its exit from the liver, also known as the pre-Erythrocytic Stage of the infection, and discuss how deciphering these interactions may contribute to our understanding of the Plasmodium parasite biology as well as to the induction of immune protection via vaccination.
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Inhibitory Effect of TNF-α on Malaria Pre-Erythrocytic Stage Development: Influence of Host Hepatocyte/Parasite Combinations
PloS one, 2011Co-Authors: Nadya Depinay, Marjorie Mauduit, Jean Francois Franetich, Anne Charlotte Grüner, Jean-marc Chavatte, Adrian J. F. Luty, Geert-jan Van Gemert, Robert W. Sauerwein, Jean-michel Siksik, Laurent HannounAbstract:BACKGROUND: The liver Stages of malaria parasites are inhibited by cytokines such as interferon-gamma or Interleukin (IL)-6. Binding of these cytokines to their receptors at the surface of the infected hepatocytes leads to the production of nitric oxide (NO) and radical oxygen intermediates (ROI), which kill hepatic parasites. However, conflicting results were obtained with TNF-alpha possibly because of differences in the models used. We have reassessed the role of TNF-alpha in the different cellular systems used to study the Plasmodium pre-Erythrocytic Stages. METHODS AND FINDINGS: Human or mouse TNF-alpha were tested against human and rodent malaria parasites grown in vitro in human or rodent primary hepatocytes, or in hepatoma cell lines. Our data demonstrated that TNF-alpha treatment prevents the development of malaria pre-Erythrocytic Stages. This inhibitory effect however varies with the infecting parasite species and with the nature and origin of the cytokine and hepatocytes. Inhibition was only observed for all parasite species tested when hepatocytes were pre-incubated 24 or 48 hrs before infection and activity was directed only against early hepatic parasite. We further showed that TNF-alpha inhibition was mediated by a soluble factor present in the supernatant of TNF-alpha stimulated hepatocytes but it was not related to NO or ROI. Treatment TNF-alpha prevents the development of human and rodent malaria pre-Erythrocytic Stages through the activity of a mediator that remains to be identified. CONCLUSIONS: Treatment TNF-alpha prevents the development of human and rodent malaria pre-Erythrocytic Stages through the activity of a mediator that remains to be identified. However, the nature of the cytokine-host cell-parasite combination must be carefully considered for extrapolation to the human infection.
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inhibitory effect of tnf α on malaria pre Erythrocytic Stage development influence of host hepatocyte parasite combinations
PLOS ONE, 2011Co-Authors: Marjorie Mauduit, Nadya Depinay, Jean Francois Franetich, Anne Charlotte Grüner, Jean-marc ChavatteAbstract:BACKGROUND: The liver Stages of malaria parasites are inhibited by cytokines such as interferon-gamma or Interleukin (IL)-6. Binding of these cytokines to their receptors at the surface of the infected hepatocytes leads to the production of nitric oxide (NO) and radical oxygen intermediates (ROI), which kill hepatic parasites. However, conflicting results were obtained with TNF-alpha possibly because of differences in the models used. We have reassessed the role of TNF-alpha in the different cellular systems used to study the Plasmodium pre-Erythrocytic Stages. METHODS AND FINDINGS: Human or mouse TNF-alpha were tested against human and rodent malaria parasites grown in vitro in human or rodent primary hepatocytes, or in hepatoma cell lines. Our data demonstrated that TNF-alpha treatment prevents the development of malaria pre-Erythrocytic Stages. This inhibitory effect however varies with the infecting parasite species and with the nature and origin of the cytokine and hepatocytes. Inhibition was only observed for all parasite species tested when hepatocytes were pre-incubated 24 or 48 hrs before infection and activity was directed only against early hepatic parasite. We further showed that TNF-alpha inhibition was mediated by a soluble factor present in the supernatant of TNF-alpha stimulated hepatocytes but it was not related to NO or ROI. Treatment TNF-alpha prevents the development of human and rodent malaria pre-Erythrocytic Stages through the activity of a mediator that remains to be identified. CONCLUSIONS: Treatment TNF-alpha prevents the development of human and rodent malaria pre-Erythrocytic Stages through the activity of a mediator that remains to be identified. However, the nature of the cytokine-host cell-parasite combination must be carefully considered for extrapolation to the human infection.