Changes in the expression of human cell division autoantigen-1 influence Toxoplasma gondii growth and development.
Toxoplasma is a significant opportunistic pathogen in AIDS, and bradyzoite differentiation is the critical step in the pathogenesis of chronic infection. Bradyzoite development has an apparent tropism for cells and tissues of the central nervous system, suggesting the need for a specific molecular environment in the host cell, but it is unknown whether this environment is parasite directed or the result of molecular features specific to the host cell itself. We have determined that a trisubstituted pyrrole acts directly on human and murine host cells to slow tachyzoite replication and induce bradyzoite-specific gene expression in type II and III strain parasites but not type I strains. New mRNA synthesis in the host cell was required and indicates that novel host transcripts encode signals that were able to induce parasite development. We have applied multivariate microarray analyses to identify and correlate host gene expression with specific parasite phenotypes. Human cell division autoantigen-1 (CDA1) was identified in this analysis, and small interfering RNA knockdown of this gene demonstrated that CDA1 expression causes the inhibition of parasite replication that leads subsequently to the induction of bradyzoite differentiation. Overexpression of CDA1 alone was able to slow parasite growth and induce the expression of bradyzoite-specific proteins, and thus these results demonstrate that changes in host cell transcription can directly influence the molecular environment to enable bradyzoite development. Investigation of host biochemical pathways with respect to variation in strain type response will help provide an understanding of the link(s) between the molecular environment in the host cell and parasite development.
Radke
Jay R
JR
Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana, USA. jradke@montana.edu
Donald
Robert G
RG
Eibs
Amy
A
Jerome
Maria E
ME
Behnke
Michael S
MS
Liberator
Paul
P
White
Michael W
MW
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics / Q000378:metabolism; D016054:DNA, Protozoan / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000469:parasitology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006790:Host-Parasite Interactions / Q000235:genetics; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014122:Toxoplasma / Q000187:drug effects / Q000254:growth & development*; D014158:Transcription, Genetic / Q000187:drug effects
D001324:Autoantigens; C106179:BAG1 protein, Toxoplasma; D016054:DNA, Protozoan; D006360:Heat-Shock Proteins; D015800:Protozoan Proteins; D011758:Pyrroles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C436320:cell division autoantigen-1; D004247:DNA