In silico identification of genetically attenuated vaccine candidate genes for Plasmodium liver stage.
Genetically attenuated parasites (GAPs) that lack genes essential for the liver stage of the malaria parasite, and therefore cause developmental arrest, have been developed as live vaccines in rodent malaria models and recently been tested in humans. The genes targeted for deletion were often identified by trial and error. Here we present a systematic gene - protein and transcript - expression analyses of several Plasmodium species with the aim to identify candidate genes for the generation of novel GAPs. With a lack of liver stage expression data for human malaria parasites, we used data available for liver stage development of Plasmodium yoelii, a rodent malaria model, to identify proteins expressed in the liver stage but absent from blood stage parasites. An orthology-based search was then employed to identify orthologous proteins in the human malaria parasite Plasmodium falciparum resulting in a total of 310 genes expressed in the liver stage but lacking evidence of protein expression in blood stage parasites. Among these 310 possible GAP candidates, we further studied Plasmodium liver stage proteins by phyletic distribution and functional domain analyses and shortlisted twenty GAP-candidates; these are: fabB/F, fabI, arp, 3 genes encoding subunits of the PDH complex, dnaJ, urm1, rS5, ancp, mcp, arh, gk, lisp2, valS, palm, and four conserved Plasmodium proteins of unknown function. Parasites lacking one or several of these genes might yield new attenuated malaria parasites for experimental vaccination studies.
Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, New Delhi 110016, India.; Integrative Parasitology, Department of Infectious Diseases, University of Heidelberg Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Hirdesh
H
Kumar
Integrative Parasitology, Department of Infectious Diseases, University of Heidelberg Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Friedrich
F
Frischknecht
Integrative Parasitology, Department of Infectious Diseases, University of Heidelberg Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Gunnar R
GR
Mair
Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, New Delhi 110016, India.. Electronic address: jgomes@bioschool.iitd.ac.in.
James
J
Gomes
D017209:Apoptosis / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D020869:Gene Expression Profiling; D006801:Humans; D008018:Life Cycle Stages / Q000235:genetics* / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000469:parasitology*; D008288:Malaria / Q000469:parasitology* / Q000517:prevention & control; D017780:Malaria Vaccines / Q000235:genetics* / Q000276:immunology; D053858:Metabolic Networks and Pathways; D058977:Molecular Sequence Annotation; D010961:Plasmodium / Q000235:genetics* / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D020543:Proteome; D040901:Proteomics / Q000379:methods; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D014613:Vaccines, Attenuated / Q000235:genetics* / Q000276:immunology
D017780:Malaria Vaccines; D020543:Proteome; D015800:Protozoan Proteins; D014613:Vaccines, Attenuated
GAPs; Ortholog based analysis; Plasmodium liver stage; Vaccine