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

Abstract

AbstractFungi 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/NFκB, 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 fungusBeauveria bassianais well-known to activate Toll-1 signalling in innate immunity inDrosophila. In fruit-flies, the adaptor Wek links Toll-1 to Sarm. Thus, here we asked whetherB. bassianacould damage theDrosophilabrain via Toll-1, Wek and Sarm. We show that exposure toB. bassianareduced fly lifespan and impaired locomotion.B. bassianaentered the brain and induced the up-regulation ofAMPs,as well aswekandsarm,within the brain. Exposure toB. bassianacaused neuronal and glial loss in the adultDrosophilabrain. Importantly, RNAi knockdown ofToll-1, wekorsarmconcomitantly with infection preventedB. bassianainduced cell loss. By contrast, over-expression ofwekorsarmwas sufficient to cause dopaminergic neuron loss in the absence of infection. These data show thatB. bassianacaused 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.