The Role of Gut-Innervating Nociceptor Neurons in Host Defense Against Salmonella Infection
Lai, Nicole Yin Yee
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CitationLai, Nicole Yin Yee. 2020. The Role of Gut-Innervating Nociceptor Neurons in Host Defense Against Salmonella Infection. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractPain-mediating nociceptor neurons are specialized sensory neurons that innervate peripheral barrier tissues, including the gastrointestinal tract, and respond to noxious/tissue-damaging stimuli to initiate protective reflexes that safeguard the host. Recent work shows that nociceptor neurons possess receptors that directly detect bacterial products to produce pain and furthermore, regulate inflammatory processes via the release of neuropeptides in peripheral tissues. Whether gut- innervating nociceptor neurons modulate host defense against enteric pathogens is unclear.
To explore the role of nociceptors in defense against the bacterial pathogen Salmonella enterica serovar Typhimurium (STm), we utilized strategies to target Nav1.8 and TRPV1 expressing sensory neurons, which led to specific ablation of these neuronal subsets in gut-extrinsic ganglia without affecting gut-intrinsic enteric neurons. Nav1.8 and TRPV1 neuron ablation in mice exacerbated STm infection resulting in higher STm colonization of the ileum, invasion of the Peyer’s patches, and dissemination to peripheral organs compared to nociceptor-sufficient counterparts.
Using 16S rRNA sequencing of duodenal, ileum, colon, and fecal samples of Nav1.8 neuron- ablated mice and control littermates, we found differences in bacterial composition that were specific to ileum tissues of nociceptor-ablated mice compared to controls. In particular, nociceptor neurons maintained the levels of Segmentous Filamentous Bacteria (SFB), a small intestinal microbe that adheres to ileum villi and Peyer’s patch epithelia. We found that SFB was necessary and sufficient for nociceptor-mediated protection against STm infection.
Nociceptor neurons also regulated the density of epithelial Microfold (M) cells in ileum Peyer’s patches. M cells are key entry points used by STm for invasion of host tissues. Nociceptor modulation of M cell density occurred upstream and independently of SFB status, however we subsequently found that M cells could modulate SFB levels. During infection, nociceptor neurons responded to STm by releasing the neuropeptide calcitonin gene-related peptide (CGRP), which regulated M cells, SFB levels, and STm host defense. These findings reveal a pathway through which nociceptor neurons modulate gastrointestinal homeostasis and protect against invading enteric pathogens. Deciphering how nociceptor neurons crosstalk with host immunological processes to defend against invading pathogens has implications for the development of host-directed therapies to control pain and treat enteric infections.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365144
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