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. Toxoplasma is a common opportunistic pathogen among immunocompromised populations that include subjects undergoing organ transplant, the fetus during early gestation, and persons with AIDS. The parasite escapes the host immune system by forming a dormant tissue cyst, and this chronic infection, as well as the clinical manifestation of disease, is observed primarily in cells and tissues of the brain and eye. Although it is not yet understood how the disease state is established, in this study researchers demonstrate that Toxoplasma can take cues from specific changes in host cell gene expression to initiate switching to the tissue cyst, and they discover that a single gene, designated human cell division autoantigen-1 (CDA1), is able to impose significant influence on the course of infection and cyst development. These studies are the first to identify a host gene that links the molecular environment in the cell to parasite development. It is interesting that the response to the host cell is not uniform among parasite strains, as acutely virulent strains appear to ignore the host and continue to proliferate until the cell is destroyed.