Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 207, Issue 1, Pages 164-174Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jis645
Keywords
NOD2; IL-17; Th17; T lymphocytes; ocular toxoplasmosis; Toxoplasma gondii
Categories
Funding
- Food and Drug Administration
- National Institutes of Health
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Background. gamma-irradiation is commonly used to create attenuation in Plasmodium parasites. However, there are no systematic studies on the survival, reversion of virulence, and molecular basis for gamma-radiation-induced cell death in malaria parasites. Methods. The effect of gamma-irradiation on the growth of asexual Plasmodium falciparum was studied in erythrocyte cultures. Cellular and ultrastructural changes within the parasite were studied by fluorescence and electron microscopy, and genome-wide transcriptional profiling was performed to identify parasite biomarkers of attenuation and cell death. Results. gamma-radiation induced the death of P. falciparum in a dose-dependent manner. These parasites had defective mitosis, sparse cytoplasm, fewer ribosomes, disorganized and clumped organelles, and large vacuoles-observations consistent with distressed or dying parasites. A total of 185 parasite genes were transcriptionally altered in response to gamma-irradiation (45.9% upregulated, 54.1% downregulated). Loss of parasite survival was correlated with the downregulation of genes encoding translation factors and with upregulation of genes associated with messenger RNA-sequestering stress granules. Genes pertaining to cell-surface interactions, host-cell remodeling, and secreted proteins were also altered. Conclusions. These studies provide a framework to assess the safety of gamma-irradiation attenuation and promising targets for genetic deletion to produce whole parasite-based attenuated vaccines.
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