Genetically Attenuated Plasmodium berghei Liver Stages Induce Sterile Protracted Protection That Is Mediated by Major Histocompatibility Complex Class I-Dependent Interferon–γ–Producing CD8+ T Cells

Jobe, Ousman; Lumsden, Joanne; Mueller, Ann-Kristin; Williams, Jackie; Silva-Rivera, Hilda; Kappe, Stefan H. I.; Schwenk, Robert J.; Matuschewski, Kai; Krzych, Urszula
August 2007
Journal of Infectious Diseases;8/15/2007, Vol. 196 Issue 4, p599
Academic Journal
At present, radiation-attenuated plasmodia sporozoites (γ-spz) is the only vaccine that induces sterile and lasting protection in malaria-naive humans and laboratory rodents. However, γ-spz are not without risks. For example, the heterogeneity of the γ-spz could explain occasional breakthrough infections. To avoid this possibility, we constructed a double-knockout P. berghei parasite by removing 2 genes, UIS3 and UIS4, that are up-regulated in infective spz.We evaluated the double-knockout Pbuis3(—)/4(—) parasites for protective efficacy and the contribution of CD8+ T cells to protection. Pbuis3(—)/4(—) spz induced sterile and protracted protection in C57BL/6 mice. Protection was linked to CD8+ T cells, given that mice deficient in β2m were not protected. Pbuis3(—)/4(—) spz-immune CD8+ T cells consisted of effector/memory phenotypes and produced interferon-γ. On the basis of these observations, we propose that the development of genetically attenuated P. falciparum parasites is warranted for tests in clinical trials as a pre-erythrocytic stage vaccine candidate.


Related Articles

  • Population Genetics of GYPB and Association Study between GYPB*S/s Polymorphism and Susceptibility to P. falciparum Infection in the Brazilian Amazon. Tarazona-Santos, Eduardo; Castilho, Lilian; Amaral, Daphne R. T.; Costa, Daiane C.; Furlani, Natália G.; Zuccherato, Luciana W.; Machado, Moara; Reid, Marion E.; Zalis, Mariano G.; Rossit, Andréa R.; Santos, Sidney E. B.; Machado, Ricardo L.; Lustigman, Sara // PLoS ONE;2011, Vol. 6 Issue 1, p1 

    Background: Merozoites of Plasmodium falciparum invade through several pathways using different RBC receptors. Field isolates appear to use a greater variability of these receptors than laboratory isolates. Brazilian field isolates were shown to mostly utilize glycophorin A-independent invasion...

  • The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Tabeta, Koichi; Hoebe, Kasper; Janssen, Edith M; Du, Xin; Georgel, Philippe; Crozat, Karine; Mudd, Suzanne; Mann, Navjiwan; Sovath, Sosathya; Goode, Jason; Shamel, Louis; Herskovits, Anat A; Portnoy, Daniel A; Cooke, Michael; Tarantino, Lisa M; Wiltshire, Tim; Steinberg, Benjamin E; Grinstein, Sergio; Beutler, Bruce // Nature Immunology;Feb2006, Vol. 7 Issue 2, p156 

    Here we have identified 'triple D' (3d), a recessive N-ethyl-N-nitrosourea-induced mutation and phenotype in which no signaling occurs via the intracellular Toll-like receptors 3, 7 and 9 (sensors for double-stranded RNA, single-stranded RNA and unmethylated DNA, respectively). The 3d mutation...

  • Haplotype variation, recombination, and gene conversion within the turkey MHC-B locus. Chaves, Lee D.; Faile, Gretchen M.; Krueth, Stacy B.; Hendrickson, Julie A.; Reed, Kent M. // Immunogenetics;Jul2010, Vol. 62 Issue 7, p465 

    The major histocompatibility complex (MHC) is a gene dense region with profound effects on the disease phenotype. In many species, characterizations of MHC polymorphisms have focused on identifying allelic haplotypes of the highly polymorphic class I and class II loci through direct...

  • Pooled Deep Sequencing of Plasmodium falciparum Isolates: An Efficient and Scalable Tool to Quantify Prevailing Malaria Drug-Resistance Genotypes. Taylor, Steve M.; Parobek, Christian M.; Aragam, Nash; Ngasala, Billy E.; Mårtensson, Andreas; Meshnick, Steven R.; Juliano, Jonathan J. // Journal of Infectious Diseases;Dec2013, Vol. 208 Issue 12, p1998 

    Molecular surveillance for drug-resistant malaria parasites requires reliable, timely, and scalable methods. These data may be efficiently produced by genotyping parasite populations using second-generation sequencing (SGS). We designed and validated a SGS protocol to quantify mutant allele...

  • SNP-o-matic. Manske, Heinrich Magnus; Kwiatkowski, Dominic P. // Bioinformatics;Sep2009, Vol. 25 Issue 18, p2434 

    Motivation: High throughput sequencing technologies generate large amounts of short reads. Mapping these to a reference sequence consumes large amounts of processing time and memory, and read mapping errors can lead to noisy or incorrect alignments. SNP-o-matic is a fast, memory-efficient and...

  • Long term persistence of clonal malaria parasite Plasmodium falciparum lineages in the Colombian Pacific region. Echeverry, Diego F; Nair, Shalini; Osorio, Lyda; Menon, Sanjay; Murillo, Claribel; Anderson, Tim JC // BMC Genetics;2013, Vol. 14 Issue 1, p1 

    Background: Resistance to chloroquine and antifolate drugs has evolved independently in South America, suggesting that genotype - phenotype studies aimed at understanding the genetic basis of resistance to these and other drugs should be conducted in this continent. This research was conducted...

  • Sequence and expression of MHC-DPB1 molecules of the New World monkey Aotus nancymaae, a primate model for Plasmodium falciparum. Diaz, Diana; Daubenberger, Claudia A.; Zalac, Tatjana; Rodriguez, Raul; Patarroyo, Manuel // Immunogenetics;Jul2002, Vol. 54 Issue 4, p251 

    Aotus nancymaae represents an animal model for the pre-clinical evaluation of blood-stage vaccine candidates against Plasmodium falciparum and Plasmodium vivax. We present here the nucleotide sequences of exon 2 and 3 of MHC-DPB1 genes. In a group of seven unrelated animals captured in the wild,...

  • Sequence and diversity of DRB genes of Aotus nancymaae, a primate model for human malaria parasites. Nino-Vasquez, J. Javier; Vogel, Denise; Rodriguez, Raul; Moreno, Alberto; Patarroyo, Manuel Elkin; Pluschke, Gerd; Daubenberger, Claudia A. // Immunogenetics;Mar2000, Vol. 51 Issue 3, p219 

    The New World primate Aotus nancymaae is susceptible to infection with the human malaria parasite Plasmodium falciparum and Plasmodium vivax and has therefore been recommended by the World Health Organization as a model for evaluation of malaria vaccine candidates. We present here a first step...

  • Interferon-γ Induces Immunoproteasomes and the Presentation of MHC I-Associated Peptides on Human Salivary Gland Cells. Arellano-Garcia, Martha E.; Misuno, Kaori; Tran, Simon D.; Hu, Shen // PLoS ONE;Aug2014, Vol. 9 Issue 8, p1 

    A prominent histopathological feature of Sjögren's syndrome, an autoimmune disease, is the presence of lymphocytic infiltrates in the salivary and lachrymal glands. Such infiltrates are comprised of activated lymphocytes and macrophages, and known to produce multiple cytokines including...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics