Genetically attenuated, P36p-deficient malarial sporozoites induce protective immunity and apoptosis of infected liver cells.

Immunization with Plasmodium sporozoites that have been attenuated by gamma-irradiation or specific genetic modification can induce protective immunity against subsequent malaria infection. The mechanism of protection is only known for radiation-attenuated sporozoites, involving cell-mediated and humoral immune responses invoked by infected hepatocytes cells that contain long-lived, partially developed parasites. Here we analyzed sporozoites of Plasmodium berghei that are deficient in P36p (p36p(-)), a member of the P48/45 family of surface proteins. P36p plays no role in the ability of sporozoites to infect and traverse hepatocytes, but p36p(-) sporozoites abort during development within the hepatocyte. Immunization with p36p(-) sporozoites results in a protective immunity against subsequent challenge with infectious wild-type sporozoites, another example of a specifically genetically attenuated sporozoite (GAS) conferring protective immunity. Comparison of biological characteristics of p36p(-) sporozoites with radiation-attenuated sporozoites demonstrates that liver cells infected with p36p(-) sporozoites disappear rapidly as a result of apoptosis of host cells that may potentiate the immune response. Such knowledge of the biological characteristics of GAS and their evoked immune responses are essential for further investigation of the utility of an optimized GAS-based malaria vaccine.

[1]  Ana Rodriguez,et al.  Apoptotic Plasmodium-infected hepatocytes provide antigens to liver dendritic cells. , 2005, The Journal of infectious diseases.

[2]  Ana Rodriguez,et al.  HGF/MET signalling protects Plasmodium‐infected host cells from apoptosis , 2005, Cellular microbiology.

[3]  S. Kappe,et al.  Plasmodium liver stage developmental arrest by depletion of a protein at the parasite-host interface. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[4]  B. Levine.  Eating Oneself and Uninvited Guests Autophagy-Related Pathways in Cellular Defense , 2005, Cell.

[5]  S. Kappe,et al.  Genetically modified Plasmodium parasites as a protective experimental malaria vaccine , 2005, Nature.

[6]  Tomoko Ishino,et al.  Liver invasion by malarial parasites – how do malarial parasites break through the host barrier? , 2004, Cellular microbiology.

[7]  R. Sinden,et al.  A malaria membrane skeletal protein is essential for normal morphogenesis, motility, and infectivity of sporozoites , 2004, The Journal of cell biology.

[8]  S. Kappe,et al.  Plasmodium sporozoite molecular cell biology. , 2004, Annual review of cell and developmental biology.

[9]  A. Morrot,et al.  Effector and memory CD8+ T cells as seen in immunity to malaria , 2004, Immunological reviews.

[10]  U. Frevert,et al.  Sneaking in through the back entrance: the biology of malaria liver stages. , 2004, Trends in parasitology.

[11]  Chris J Janse,et al.  A Plasmodium berghei reference line that constitutively expresses GFP at a high level throughout the complete life cycle. , 2004, Molecular and biochemical parasitology.

[12]  S. Frank,et al.  Apoptosis is essential for the increased efficacy of alphaviral replicase-based DNA vaccines. , 2004, Vaccine.

[13]  G. DeAngelis,et al.  Perceptual “Read-Out” of Conjoined Direction and Disparity Maps in Extrastriate Area MT , 2004, PLoS biology.

[14]  Simona Corso,et al.  Hepatocyte growth factor and its receptor are required for malaria infection , 2003, Nature Medicine.

[15]  S. Hoffman,et al.  Rationale and plans for developing a non-replicating, metabolically active, radiation-attenuated Plasmodium falciparum sporozoite vaccine , 2003, Journal of Experimental Biology.

[16]  Patricia De la Vega,et al.  Discovery of Gene Function by Expression Profiling of the Malaria Parasite Life Cycle , 2003, Science.

[17]  M. Tsuji,et al.  T cells as mediators of protective immunity against liver stages of Plasmodium. , 2003, Trends in parasitology.

[18]  J. Blaho.  VIRUS INFECTION AND APOPTOSIS (ISSUE I): AN INTRODUCTION , 2003 .

[19]  S. Levy,et al.  Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity , 2003, Nature Medicine.

[20]  Ana Rodriguez,et al.  Migration through host cells activates Plasmodium sporozoites for infection , 2002, Nature Medicine.

[21]  R. Ménard,et al.  Plasmodium sporozoite invasion into insect and mammalian cells is directed by the same dual binding system , 2002, The EMBO journal.

[22]  M. Tsuji,et al.  Detection of malaria liver-stages in mice infected through the bite of a single Anopheles mosquito using a highly sensitive real-time PCR. , 2001, International journal for parasitology.

[23]  U. Groß,et al.  Intracellular protozoan parasites and apoptosis: diverse strategies to modulate parasite-host interactions. , 2001, Trends in parasitology.

[24]  J. Adams,et al.  Exploring the transcriptome of the malaria sporozoite stage , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  R. Carter,et al.  Current developments in malaria transmission-blocking vaccines , 2001, Expert opinion on biological therapy.

[26]  C. Janse,et al.  Functional Equivalence of Structurally Distinct Ribosomes in the Malaria Parasite, Plasmodium berghei * , 2001, The Journal of Biological Chemistry.

[27]  R. Ménard,et al.  Gliding motility and cell invasion by Apicomplexa: insights from the Plasmodium sporozoite , 2001, Cellular microbiology.

[28]  M. Tsuji,et al.  Progress toward a Malaria Vaccine: Efficient Induction of Protective Anti-Malaria Immunity , 2001, Biological chemistry.

[29]  H. Stunnenberg,et al.  A Central Role for P48/45 in Malaria Parasite Male Gamete Fertility , 2001, Cell.

[30]  B. Metscher,et al.  [Dexketoprofen-trometamol and tramadol in acute lumbago]. , 2001, Fortschritte der Medizin. Originalien.

[31]  M. Mota,et al.  Migration of Plasmodium sporozoites through cells before infection. , 2001, Science.

[32]  C. van Overmeir,et al.  Rodent malaria in the natural host--irradiated sporozoites of Plasmodium berghei induce liver-stage specific immune responses in the natural host Grammomys surdaster and protect immunized Grammomys against P. berghei sporozoite challenge. , 2001, African journal of medicine and medical sciences.

[33]  N. Restifo.  Building better vaccines: how apoptotic cell death can induce inflammation and activate innate and adaptive immunity. , 2000, Current opinion in immunology.

[34]  R. Ménard,et al.  The selectable marker human dihydrofolate reductase enables sequential genetic manipulation of the Plasmodium berghei genome. , 2000, Molecular and biochemical parasitology.

[35]  S. Hoffman,et al.  IL-12 and NK cells are required for antigen-specific adaptive immunity against malaria initiated by CD8+ T cells in the Plasmodium yoelii model. , 1999, Journal of immunology.

[36]  C. Janse,et al.  Analysis of stage specificity of promoters in Plasmodium berghei using luciferase as a reporter. , 1999, Molecular and biochemical parasitology.

[37]  R. Ménard,et al.  Gene targeting in malaria parasites. , 1997, Methods.

[38]  Andrea Crisanti,et al.  TRAP Is Necessary for Gliding Motility and Infectivity of Plasmodium Sporozoites , 1997, Cell.

[39]  A. Azad,et al.  Maintenance of protective immunity against malaria by persistent hepatic parasites derived from irradiated sporozoites. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[40]  C. Janse,et al.  Plasmodium berghei: the application of cultivation and purification techniques to molecular studies of malaria parasites. , 1995, Parasitology today.

[41]  M. J. Stewart,et al.  Malaria sporozoites leave behind trails of circumsporozoite protein during gliding motility. , 1988, The Journal of protozoology.

[42]  R. Sinden,et al.  The complete development in vitro of the vertebrate phase of the mammalian malarial parasite Plasmodium berghei. , 1987, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[43]  R. Gwadz,et al.  Simple centrifugation method for rapid separation of sporozoites from mosquitoes. , 1984, The Journal of parasitology.

[44]  R. Nussenzweig,et al.  Comparative studies on the immunogenicity of infective and attenuated sporozoites of Plasmodium berghei. , 1982, Transactions of the Royal Society of Tropical Medicine and Hygiene.