Changes in the Expression of Human Cell Division Autoantigen-1 Influence Toxoplasma gondii Growth and Development

Abstract

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.

Inhibitors of eIF2α Dephosphorylation Slow Replication and Stabilize Latency in Toxoplasma gondii

“…First, we reasoned that if SAL and GA function through the host cells, treatment with either drug prior to infection may affect parasite replication. Such effects of drug preconditioning were reported by Radke et al, who demonstrated that pretreatment of HFF host cells with compound 1 (a trisubstituted pyrrole and bradyzoite inducer) prior to infection with tachyzoites reduced parasite proliferation by promoting bradyzoite formation (18). We therefore pretreated HFF monolayers with increasing concentrations of SAL, GA, or vehicle for 24 h prior to infection and then counted the number of parasites per vacuole 24 h postinfection.…”

Modulation of the Host Cell Proteome by the Intracellular Apicomplexan ParasiteToxoplasma gondii

“…We have recently obtained evidence that T. gondii infection promotes the G 1 -to-S transition in infected HFFs (R. E. Molestina, E. I. Guendy, and A. P. Sinai, unpublished data). Toxoplasma infection does not promote the replication of the infected cell, unlike the related Apicomplexa of Theileria species (22), but clearly is influenced by cell cycle modulators, as seen with the overexpression of the CDA1 gene promoting cystogenesis (71). …”

New insights into type II germ cell tumor pathogenesis based on studies of patients with various forms of disorders of sex development (DSD)

“…TSPY is homologous to SET/NAP proteins, which play a role in nucleosome assembly and chromatin remodelling (Wagner et al, 2006). Next to some pseudogenes, also a functional X chromosomal homolog of TSPY exists in humans (called TSPYlike 2 or TSPX, DENTT, hCINAP, CDA1, se20-4), which, in contrast to TSPY, is widely expressed and plays a role in growth arrest, TGFbeta1 signalling and regulates growth and differentiation of the intracellular parasite toxoplasma gondii (Chai et al, 2001;Ozbun et al, 2005;Radke et al, 2006).…”