Staphylococcus aureus-Induced Degeneration of Nociceptive Neurons in Caenorhabditis elegans

In all animals, the nervous system senses microbial signals to influence host defense. Despite emerging as important sensors of infection to regulate immunity and inflammation, the mechanisms by which pain-sensing nociceptor neurons can detect infections are poorly defined. Using C. elegans as a tractable model host that shares many features with mammalian systems, we investigated nociceptor function during bacterial infection.

In vivo intracellular Ca²⁺ imaging of nociceptor ASH neurons revealed a drastic reduction in ASH responses to aversive stimuli in Staphylococcus aureus-infected animals compared to noninfected controls. Morphological examination showed that the ASH neurons lost integrity in the sensory processes that extend to the mouth, in a pathogen growth phase-dependent manner. Neighboring neurons did not exhibit this pathogen-induced neurodegeneration (PaIN) phenotype. Genetic analysis suggested that apoptosis, necrosis, ferroptosis, and autophagy are dispensable for the PaIN phenotype. In contrast, loss of the evolutionarily conserved stress-response transcription factor HLH-30/TFEB reduced the penetrance of ASH PaIN by about 50%. Moreover, infected animals showed defective ASH-mediated evasive behaviors, suggesting that the S. aureus-triggered drop in ASH activation and morphological degeneration are physiologically relevant.

Collectively, these findings reveal that nociceptor neurons lose functional and morphological integrity during infection with S. aureus, with severe consequences for animal behavior. Because S. aureus is a critical human pathogen, the induction of nociceptor PaIN may have important implications for human health.