Research

What has become apparent over the last decade of research is that T. gondii has evolved an extensive battery of complex molecular tools that it releases into its host cell to directly influence defense signaling pathways to avoid immunological clearance, facilitate chronic infection, and thus ensure disease transmission. We are using multidisciplinary approaches including genome-wide genetic screens, proteomics, cell biology, microscopy, and biochemistry to uncover novel T. gondii secreted effectors and understand their mechanism of action.

A critical factor in the transmission and pathogenesis of T. gondii is its ability to convert from an acute disease-causing, proliferative stage (tachyzoite) to a chronic, semi-dormant stage (bradyzoite) in host muscle and neuronal cells. The chronic stage is refractory to current treatments and can also reactivate in immunocompromised hosts, leading to a potentially fatal outcome. Yet, despite its critical role in Toxoplasmosis pathology, the bradyzoite interaction with neuronal cells at the molecular and cellular levels is critically understudied. Utilizing a newly developed primary cortical neuron culture system along with neuronal cell line protocols we will study the effects of T. gondii on neuronal transcription, epigenetic status and cell biology.

Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioral processes. The central circadian clock exerts control over myriad aspects of mammalian physiology, including the regulation of sleep, metabolism, and the immune system. In the case of host-microbe interactions, many studies have shown that the outcome of an infection (whether bacterial, viral, or parasitic) depends on the time of day at which the infection is initiated. In mammals, circadian rhythms are regulated by intricate feedback loops. The core of the first loop involves two transcription factors, CLOCK and BMAL1, and their repressors, PER and CRY. A second regulatory loop involves the nuclear receptors REV-ERBs and RORs, which bind to BMAL1 promoter to drive its rhythmic transcription. REV-ERBs are dedicated repressors of transcription that mediate their effect through interaction with the NCoR/SMRT complex. In our preliminary experiments, we found that T. gondii’s recently discovered secreted effector TgNSM (T. gondii NCoR/SMRT modulator) enhances REV-ERBs repression of the BMAL1 promoter transcription, leading to an increased amplitude of BMAL1 promoter driven circadian rhythms. We aim to understand the crosstalk between the host circadian clock and T. gondii infection.