differential, positional-dependent transcriptional response of antigenic variation (var) genes to biological stress in plasmodium falciparum微分,positional-dependent转录反应的抗原变异(var)基因在恶性疟原虫生物应力.pdfVIP

Differential, Positional-Dependent Transcriptional Response of Antigenic Variation (var) Genes to Biological Stress in Plasmodium falciparum 1. 1. 1 1 2 1. Elli Rosenberg , Amir Ben-Shmuel , Oshrit Shalev , Rosa Sinay , Alan Cowman , Yaakov Pollack * 1The Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of the Negev, Beer-Sheva, Israel, 2 Department of Infection and Immunity, The Walter Eliza Hall Institute of Medical Research, Melbourne, Australia Abstract 1% of the genes of the human malaria causing agent Plasmodium falciparum belong to the heterogeneous var gene family which encodes P. falciparum erythrocyte membrane protein 1 (PFEMP1). This protein mediates part of the pathogenesis of the disease by causing adherence of infected erythrocytes (IE) to the host endothelium. At any given time, only one copy of the family is expressed on the IE surface. The cues which regulate the allelic exclusion of these genes are not known. We show the existence of a differential expression pattern of these genes upon exposure to biological stress in relation to their positional placement on the chromosome – expression of centrally located var genes is induced while sub-telomeric copies of the family are repressed - this phenomenon orchestrated by the histone deacetylase pfsir2. Moreover, stress was found to cause a switch in the pattern of the expressed var genes thus acting as a regulatory cue. By using pharmacological compounds which putatively affect pfsir2 activity, distinct changes of var gene expression patterns were achieved which may have therapeutic ramifications. As disease severity is partly associated with expression of particular var gene