Fungi exploit natural defence to induce neuronal and glial loss in Drosophila brain

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Singh, Deepanshu (2023). Fungi exploit natural defence to induce neuronal and glial loss in Drosophila brain. University of Birmingham. Ph.D.

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Abstract

Parasites have evolved behaviour manipulation strategies to exploit their host for nutrition and reproduction. In Drosophila, the fungus Enthomophthora muscae affects the nervous system altering behaviour (Carolyn et al., 2018). Furthermore, volatile compounds produced by fungi can cause dopaminergic neuron loss and locomotion deficits, reminiscent of Parkinsonism (Inamdar et al., 2013). In humans, genetics accounts for a small fraction of Parkinson’s disease onset and environmental triggers are likely a common cause. How fungi affect the brain and the causal links between cellular phenotypes and behaviour are poorly understood.

Innate immune response is the first line of defence against a pathogenic infection which is mediated by Toll signalling. Tolls are evolutionary conserved and have varied functions from immunity to regulation of cell number plasticity regulated via different pathways. The fungus Beauveria bassiana is a known activator of Toll signalling in Drosophila and Tolls are present throughout the brain. Thus, the aim of the thesis is to investigate whether B. bassiana alters the fruit-fly brain by exploiting Toll signalling.

Here, I provide evidence that upon natural exposure to B. bassiana, the spores enter the brain. B. bassiana spores could enter into the brain through feeding and damage the blood brain barrier. Exposure causes neuronal and glial loss, loss of the dopaminergic neurons and a decrease in brain size over time. Expression of anti-microbial peptides is upregulated in the brain upon B. bassiana exposure, demonstrating activation of Toll signalling. Importantly, expression of the pro-apoptotic Toll signalling adaptors sarm and wek (Foldi et al., 2017) is also upregulated. These neurodegeneration phenotypes correlate with impaired locomotion and shorter lifespan. Furthermore, upon downregulating the expression of Toll-1, wek or sarm, B. bassiana cannot induce cells and dopaminergic neurons loss in the adult Drosophila brain. This indicates the non-canonical Toll signalling Wek and Sarm could have a role in B.bassiana induced neuronal and glial cell loss in the adult Drosophila brain.

Together these findings reveal that fungi exploited an evolutionary opportunity to bypass defence to their advantage.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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