Abstract
Toxoplasma 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. Chronic stages are established by differentiation of rapidly replicating tachyzoites into slow-growing bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies. Despite its central role in infection, the molecular basis of chronic differentiation is not understood. Through Cas9-mediated genetic screening and single-cell transcriptional profiling, we identify and characterize a putative transcription factor (BFD1) as necessary and sufficient for differentiation. Translation of BFD1 appears to be stress regulated, and its constitutive expression elicits differentiation in the absence of stress. As a Myb-like factor, BFD1 provides a counterpoint to the ApiAP2 factors which dominate our current view of parasite gene regulation. Overall, BFD1 provides a genetic switch to study and control Toxoplasma differentiation, and will inform prevention and treatment of chronic infection.
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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