Pain is a fundamental protective neuronal signal for organisms to avoid danger. Nociceptors are the specific subset of peripheral sensory neurons that detect harmful/noxious stimuli and transmit pain signals to the brain. Chronic pain is a major socio-economic burden, but the underlying molecular mechanisms are not well understood. I previously found that bacterial pathogens produced pain by directly activating nociceptor neurons during infection. Moreover, I found that nociceptors played a role in suppressing local immune cell recruitment and lymphadenopathy. These findings raise the possibility that the nervous system can play a direct participatory role in host defense. Nociceptor neurons densely innervate the skin and gut, which are heavily colonized by commensal bacteria. However, the bidirectional crosstalk between the tissue-resident microbes with the sensory nervous system is poorly understood. In this NIH Director's New Innovator Award, I test the hypothesis that molecular interactions between the host microbiota and nociceptor neurons play a key role in governing pain production and the composition of the microbiota. This research is motivated by basic questions about the role of host-microbe interactions that will help us gain insights into mammalian physiology: i) Do specific commensal gut or skin bacterial species (pathobionts or symbionts) set the threshold for nociceptor neuron activity and development of chronic pain? ii) Can we identify specific bacterial molecular mediators that modulate nociceptor neural activity and pain? iii) Do nociceptor-associated ligands in spicy foods (e.g. capsaicin, mustard oil) have a significant impact on the composition and quality of the microbiota? Iv) Do nociceptor neurons produce molecular mediators that directly impact the microbiota or tissue-resident immune cells? To address these questions, I will combine neurobiological, immunological, and microbiological approaches to analyze the reciprocal interactions between nociceptor neurons and the resident microbiota. Germ-free and bacterial monocolonization experiments will determine if distinct symbiotic or pathobiotic commensal bacterial strains influence the development of pain. Neuronal calcium flux, multi-electrode array analysis, and protein chemical techniques will define the bacterial mediators that modulate nociceptor activity. These analyses will lead to the identification of potential novel molecular mediators of pain. Conversely, I will analyze if nociceptor activity in vivo plays a role in regulating the host microbiota. Using transgenic, pharmacological, and optogenetic strategies to specifically deplete, activate or silence nociceptors, I will ascertain whether sensory neurons modulate the composition of the skin and gut microbiota. Based on my foundational training in Immunology and Neurobiology, along with the ability to carry out cross-disciplinary scientific approaches, I am uniquely qualified to lead this effort. I have demonstrated a willingness to challenge convential paradigms, focusing my research on questions that have potential impacts on human health. With this proposed NIH Director's New Innovator Award, I will carry out studies to produce novel insights into host- microbe interactions facilitating the development of treatments for chronic pain and microbial dysbiosis.

Public Health Relevance

Chronic pain is a major public health issue with significant medical and economic costs. Pain is mediated by nociceptor sensory neurons that innervate barrier tissues heavily colonized by microbes, but the biological relationship of nociceptors with the commensal microbiota is not known. In this proposal, I will analyze the role of neuron-bacteria interactions in pain and microbial homeostasis through experiments that will 1) Identify specific commensal bacterial strains and their molecular mediators that influence pain production, and 2) Determine whether nociceptor neurons play a role in regulating the composition and quality of the microbiota, thus generating novel insights into host-microbe interactions that could produce novel therapies for pain and inflammation.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
3DP2AT009499-01S1
Application #
9869280
Study Section
Program Officer
Kim, Hye-Sook
Project Start
2016-09-30
Project End
2021-06-30
Budget Start
2019-09-04
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Baral, Pankaj; Umans, Benjamin D; Li, Lu et al. (2018) Nociceptor sensory neurons suppress neutrophil and ?? T cell responses in bacterial lung infections and lethal pneumonia. Nat Med 24:417-426
Chavan, Sangeeta S; Ma, Pingchuan; Chiu, Isaac M (2018) Neuro-immune interactions in inflammation and host defense: Implications for transplantation. Am J Transplant 18:556-563
Pinho-Ribeiro, Felipe A; Baddal, Buket; Haarsma, Rianne et al. (2018) Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection. Cell 173:1083-1097.e22
Blake, Kimbria J; Baral, Pankaj; Voisin, Tiphaine et al. (2018) Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314. Nat Commun 9:37
Chiu, Isaac M (2018) Infection, Pain, and Itch. Neurosci Bull 34:109-119
Voisin, Tiphaine; Bouvier, Amélie; Chiu, Isaac M (2017) Neuro-immune interactions in allergic diseases: novel targets for therapeutics. Int Immunol 29:247-261
Yang, Nicole J; Chiu, Isaac M (2017) Bacterial Signaling to the Nervous System through Toxins and Metabolites. J Mol Biol 429:587-605
Pinho-Ribeiro, Felipe A; Verri Jr, Waldiceu A; Chiu, Isaac M (2017) Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation. Trends Immunol 38:5-19
Lai, N Y; Mills, K; Chiu, I M (2017) Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence. J Intern Med 282:5-23
Yissachar, Nissan; Zhou, Yan; Ung, Lloyd et al. (2017) An Intestinal Organ Culture System Uncovers a Role for the Nervous System in Microbe-Immune Crosstalk. Cell 168:1135-1148.e12

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