Chris Tonkin-Projects

Chris Tonkin-Projects


How do parasites sense their environment to regulate motility and invasion?

Throughout their complex lifecycles apicomplexan parasites pass between different hosts and encounter vastly different environments, triggering developmental progression and infectivity. This allows for their survival and propagation. Without their ability to sense environmental cues the life cycle of parasites is interrupted and they cannot survive. 

Understanding the identity of environmental cues and the mechanisms parasites use to sense these remains one of the major gaps in our fundamental understanding of the pathogenesis across Apicomplexa. Furthermore, such signalling pathways offer a rich new source of drug and vaccine targets to prevent or treat infection. 

Our current efforts in this area lie in understanding how parasites sense environmental cues to activate and switch off motility to regulate host cell invasion. 

We utilise the powerful forward and reverse genetics and experimental tractability of Toxoplasma to understand the molecular basis of environmental sensing and signal transduction and how this process is conserved across apicomplexan species. 

Central to signal transduction and activation of invasion is Ca2+ signalling and we continue to develop and adapt tools to probe the nature of this pathway (for example, the use of genetically encoded biosensors). 

We are also interested in understanding how parasites produce the force required for motility and invasion. The actomyosin-based ‘glideosome’ drives parasite motility and consists of a myosin anchored to the parasite periphery by the glideosome associated protein (GAP) complex. The myosin is made up of an unusual ‘type XIV’ heavy chain - MyoA - bound by two light chains. 

We are interested in defining how the MyoA produces force to drive motility. Here we use a combination of structural biology, parasite molecular biology and biophysics to understand how force is produced to drive apicomplexan motility and therefore provide a foundation in which to develop new drugs that prevent motility and invasion.

How does latent Toxoplasma persist and cause brain dysfunction?

Acute toxoplasmosis is most often self-resolving but always results in a latent infection that persists for life in the muscle and central nervous system (CNS).

Latent Toxoplasma then acts as a reservoir for acute-stage reactivation which can cause disease in immunocompromised patients and those undergoing chemotherapy.

Latent infection in the eye is a major cause of progressive blindness through the destruction of infected retinal tissue. More recently, latent Toxoplasma infection has also been associated with several neuropsychiatric conditions including schizophrenia and Alzheimer’s disease, suggesting that chronic infection has a bigger effect on human health than previously thought. There are no known treatments to clear latent Toxoplasma in at-risk patients.

We are interested in understanding how Toxoplasma persists in the human host and furthermore, what consequences this infection has on brain health. We are focussed on defining the mechanisms used by latent Toxoplasma to manipulate host neurons and the functional importance this has on parasite survival. In particular we are interested in identifying parasite proteins that are exported into neurons and what role these proteins play in allowing long term survival in the brain. Furthermore, we aim to determine how latent forms regulate metabolism, which may aid their resistance to drugs that target acute stages.

We are also defining how latent Toxoplasma can contribute to brain dysfunction. In particular, we aim to understand how Toxoplasma affects neuronal function and how this translates into changes seen in neuropsychiatric conditions. We have collaborations with leading neuroscientists to understand how Toxoplasma can cause behavioural deficits associated with schizophrenia, determine the role that infection plays in the progression of Alzheimer’s disease and furthermore, how latent toxoplasmosis effects outcomes of traumatic brain injury.