Abstract
SummaryToxoplasma gondii chronically infects a quarter of the world’s population, and its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent. Acute-stage tachyzoites differentiate into chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies. The molecular basis of this differentiation is unknown, despite being efficiently triggered by stresses in culture. Through Cas9-mediated screening and single-cell profiling, we identify a Myb-like transcription factor (BFD1) necessary for differentiation in cell culture and in mice. BFD1 accumulates during stress and its synthetic expression is sufficient to drive differentiation. Consistent with its function as a transcription factor, BFD1 binds the promoters of many stage-specific genes and represents a counterpoint to the ApiAP2 factors that dominate our current view of parasite gene regulation. BFD1 provides a genetic switch to study and control Toxoplasma differentiation and will inform prevention and treatment of chronic infections.
Highlights
The duration of infection is a critical parameter in the evolutionary fitness of infectious organisms
Plasmodium vivax hypnozoites in the liver are resistant to many antimalarial therapies, leading to long periods of latency followed by the patent infection, complicating eradication efforts (Baird, 2009)
2% of infections result in ocular lesions—a leading cause of infectious blindness—with high rates of reactivation from chronic stages that persist after treatment (Jones et al, 2015)
Summary
The duration of infection is a critical parameter in the evolutionary fitness of infectious organisms. Pathogens can extend the period of infection by establishing a latent or chronic state, avoiding clearance through slow replication, altered immunogenicity, and a diminished impact on the host. These reservoirs are frequently resistant to treatment due to decreased metabolic rates. A proportion of tachyzoites differentiate into slow-growing bradyzoites, forming intracellular cysts with a tropism for brain and muscle tissue (Dubey et al, 1998) These cysts cannot be completely eliminated by the immune system or by current therapies, and, as a result, up to a quarter of the world’s population is chronically infected with Toxoplasma (Montoya and Liesenfeld, 2004). 2% of infections result in ocular lesions—a leading cause of infectious blindness—with high rates of reactivation from chronic stages that persist after treatment (Jones et al, 2015)
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