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bioRxiv · 10.1101/2024.04.29.591341

Fungi activate Toll-1 dependent immune evasion to induce cell loss in the host brain

Singh, D. N. D.·Roberts, A. R. E.·Quesada Moraga, E.·Alliband, D.·Ballou, E. R.·Tsai, H.-J.·Hidalgo, A.
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Abstract

Fungi evolve within the host, ensuring their own nutrition and reproduction, at the expense of host health. They intervene in hosts brain function, to alter host behaviour and induce neurodegeneration. In humans, fungal infections are emerging as drivers of neuroinflammation, neurodegenerative diseases and psychiatric disorders. However, how fungi alter the host brain is unknown. Fungi trigger an innate immune response mediated by the Toll-1/TLR receptor, the adaptor MyD88 and the transcription factor Dif/NF{kappa}B, that induce the expression of antimicrobial peptides (AMPs). However, in the nervous system, Toll-1/TLR could also drive an alternative pathway involving the adaptor Sarm, which causes cell death instead. Sarm is the universal inhibitor of MyD88 and could drive immune evasion. The entomopathogenic fungus Beauveria bassiana is well-known to activate Toll-1 signalling in innate immunity in Drosophila. In fruit-flies, the adaptor Wek links Toll-1 to Sarm. Thus, here we asked whether B. bassiana could damage the Drosophila brain via Toll-1, Wek and Sarm. We show that exposure to B. bassiana reduced fly lifespan and impaired locomotion. B. bassiana entered the brain and induced the up-regulation of AMPs, as well as wek and sarm, within the brain. Exposure to B. bassiana caused neuronal and glial loss in the adult Drosophila brain. Importantly, RNAi knockdown of Toll-1, wek or sarm concomitantly with infection prevented B. bassiana induced cell loss. By contrast, over-expression of wek or sarm was sufficient to cause dopaminergic neuron loss in the absence of infection. These data show that B. bassiana caused cell loss in the host brain via Toll-1/Wek/Sarm signalling driving immune evasion. We conclude that pathogens can benefit from an innate immunity receptor to damage the host brain. A similar activation of Sarm downstream of TLRs in response to fungal infections could underlie psychiatric and neurodegenerative diseases in humans.

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Singh, D. N. D., Roberts, A. R. E., Quesada Moraga, E., Alliband, D., Ballou, E. R., Tsai, H.-J., Hidalgo, A.. 2024-04-30. Fungi activate Toll-1 dependent immune evasion to induce cell loss in the host brain. https://doi.org/10.1101/2024.04.29.591341

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