Fig. 1.

Nociceptor neurons directly detect pathogens and their molecular ligands to mediate pain. Nociceptor sensory nerve terminals directly detect bacterial, fungal, and viral pathogens or their molecular ligands through several mechanisms. Lipopolysaccharide (LPS), a major cell wall component of gram-negative bacteria, binds to neuronal TLR4 to sensitize the TRPV1 ion channel, or directly mediates the opening of the TRPA1 ion channel. Staphylococcus aureus activates nociceptor neurons through bacterial N-formyl peptides that bind to FPR1 or through binding of the pore-forming toxin α-hemolysin to ADAM10. Bacterial flagellin activates TLR5 in Aβ fibers involved in neuropathic pain production. Candida albicans activates nociceptors through the cell-wall component zymosan. Herpesviruses produce significant pain during acute infection, and infection can result in post-herpetic neuralgia characterized by chronic pain. Mycobacterium ulcerans releases a mycolactone that silences pain through signaling downstream of the angiotensin II receptor (ATR2), leading to neuronal hyperpolarization.