A/Prof Chris Tonkin, Division Head | WEHI Researcher Profile

Q: 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.

About

Our lab aims to reveal fundamental molecular mechanisms underlying pathogenesis in the Apicomplexa – a collection of notorious human and animal parasites. Apicomplexan parasites are related based on similarities in their infection mechanism and include Plasmodium spp (malaria), Cryptosporidium spp (severe diarrhoea) and Toxoplasma gondii (toxoplasmosis).

We use a range of molecular and biochemical techniques to unveil essential processes that govern their behaviour and ability to thwart our body’s defences. Our aim is to find chinks in their armour to use for therapeutic advantage.

The lab has broad interests and currently focusses on the following questions:
* How do parasites sense their environment to regulate motility and invasion?
* How does latent Toxoplasma persist and cause brain dysfunction?

Education

Publications

Selected publications from A/Prof Chris Tonkin

Baker TL, Wright DK, Thergarajan P, Uboldi AD, Vo A, Wilson T, Tonkin CJ, O’Brien TJ, Antonic-Baker A, Asmussen MJ, McDonald SJ, Casillas-Espinosa PM, Jones NC, Ali I, Sun M, Shultz SR. A pre-existing chronic Toxoplasma gondii infection promotes epileptogenesis and neuropathology in a mouse model of mesial temporal lobe epilepsy. Brain Behavior and Immunity. 2025;128:10.1016/j.bbi.2025.04.026

Liyanage KLDTD, Amery-Gale J, Uboldi AD, Adriaanse K, Firestone SM, Tonkin CJ, Jabbar A, Hufschmid J. Seroprevalence and risk factors for Toxoplasma gondii exposure in Australian feral and stray cats using an in-house modified agglutination test. Veterinary Parasitology. 2024;332:10.1016/j.vetpar.2024.110306

Baker TL, Wright DK, Uboldi AD, Tonkin CJ, Vo A, Wilson T, McDonald SJ, Mychasiuk R, Semple BD, Sun M, Shultz SR. A pre-existing Toxoplasma gondii infection exacerbates the pathophysiological response and extent of brain damage after traumatic brain injury in mice. Journal of Neuroinflammation. 2024;21(1):10.1186/s12974-024-03014-w

Seizova S, Ferrel A, Boothroyd J, Tonkin CJ. Toxoplasma protein export and effector function. Nature Microbiology. 2024;9(1):10.1038/s41564-023-01563-z

Wilde M-L, Ruparel U, Klemm T, Lee VV, Calleja DJ, Komander D, Tonkin CJ. Characterisation of the OTU domain deubiquitinase complement of Toxoplasma gondii. Life Science Alliance. 2023;6(6):10.26508/lsa.202201710

Dans MG, Piirainen H, Nguyen W, Khurana S, Mehra S, Razook Z, Geoghegan ND, Dawson AT, Das S, Schneider MP, Jonsdottir TK, Gabriela M, Gancheva MR, Tonkin CJ, Mollard V, Goodman CD, McFadden GI, Wilson DW, Rogers KL, Barry AE, Crabb BS, de Koning-Ward TF, Sleebs BE, Kursula I, Gilson PR. Sulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics. PLOS Biology. 2023;21(4):10.1371/journal.pbio.3002066

John A, Bader SM, Soler NM, Wiradiputri K, Tichkule S, Smyth ST, Ralph SA, Jex AR, Scott NE, Tonkin CJ, Goddard-Borger ED. Conservation, abundance, glycosylation profile, and localization of the TSP protein family in Cryptosporidium parvum. Journal of Biological Chemistry. 2023;299(3):10.1016/j.jbc.2023.103006

Tsee Dawson A, Tonkin CJ. A CRISPR upgrade unlocks Toxoplasma gene function. Trends in Parasitology. 2022;38(10):10.1016/j.pt.2022.07.007

Jex AR, Tonkin CJ, Ralph SA. 3, 2, 1, go! Cryptosporidium counts down to sex. PLOS Biology. 2022;20(5):10.1371/journal.pbio.3001638

Seizova S, Ruparel U, Garnham AL, Bader SM, Uboldi AD, Coffey MJ, Whitehead LW, Rogers KL, Tonkin CJ. Transcriptional modification of host cells harboring Toxoplasma gondii bradyzoites prevents IFN gamma-mediated cell death. Cell Host & Microbe. 2022;30(2):10.1016/j.chom.2021.11.012

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Lab research 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?

Student research projects

Investigating host ubiquitin ligases in fighting Toxoplasma infections

PhD

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Investigating host ubiquitin ligases in fighting Toxoplasma infections

PhD

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A/Prof Chris Tonkin

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