#  Nociceptor sensing of bacterial pathogens in pain and host defense 

 



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 Nociceptors are the peripheral sensory neurons that detect noxious/harmful stimuli and mediate pain. We have discovered that nociceptors directly sense microbial pathogens and their toxins to produce pain. In mouse model of infection, *S. aureus* directly activates nociceptors through the pore-forming toxin a-hemolysin and N-formylated peptides to produce pain. We also have found that the gram-positive pathogen *S. pyogenes* activates nociceptors via its secreted toxin streptolysin S. Upon activation, nociceptors release neuropeptides including calcitonin gene-related peptide (CGRP), which signals to innate immune cells to regulate bacterial host defenses. Targeting this neuroimmune signaling can lead to enhanced neutrophil recruitment and function during infection. We recently found that *B. anthracis* anthrax toxin can directly regulate pain signaling and that engineered anthrax toxins can deliver molecular cargoes into neurons to silence pain Defining how neurons sense microbes and crosstalk with immune cells could lead to novel approaches to treat pain and infectious diseases. We are also now investigating how the bacterial pathogen *Borrelia burgdorferi*, the causative agent of Lyme Disease, could interact with the nervous system in pain and host defense.

   ![daping_pic.jpg](/sites/g/files/omnuum8911/files/styles/hwp_1_1__360x360_scale/public/chiu/files/daping_pic.jpg?itok=u79YY5U0) 

 

   ![pain_diagram.jpg](/sites/g/files/omnuum8911/files/styles/hwp_1_1__360x360_scale/public/chiu/files/pain_diagram.jpg?itok=U_5CXlzb) 

 

 Publications on this topic:

1. **Chiu IM,** Heesters B, Ghasemlou N, Von Hehn CA, Zhao F, Tran J, Wainger BW, Strominger A, Muralidharan S, Horswill A, Bubeck Wardenburg JA, Carroll MC, Hwang SW, Woolf CJ. Bacteria activate sensory neurons that modulate pain and inflammation. *Nature.* 2013 Sep 5; 501(7465): 52-7. PMCID: [PMC3773968](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773968/).  [PDF](/files/chiu_et_al_2013_nature_01.pdf)
2. Blake KJ, Baral P, Voisin T, Lubkin A, Pinho-Ribeiro FA, Adams KL, Roberson DP, Ma YC, Otto M, Woolf CJ, Torres VJ, **Chiu IM**. *Staphylococcus aureus* produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314. *Nature Communications.* 2018 Jan 2;9(1):37. PMCID: [PMC5750211](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750211/).  [PDF](/files/blake_et_al_2018_nat_commun_0.pdf)
3. Pinho-Ribeiro FA, Baddal B, Haarsma R, O’Seaghdha M, Yang NJ, Blake KJ, Portley M, Verri Jr. WA, Dale JB, Wessels MR, **Chiu IM**. Blocking neuronal signaling to immune cells treats streptococcal invasive infection. *Cell.* 2018 May 17;173(5):1083-1097. PMCID: [PMC5959783](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959783/).  [PDF](/file_url/177)
4. Yang NJ, Neel DV, Deng L, Heyang M, Kennedy-Curran A, Tong VS, Park JM, **Chiu IM**. Nociceptive sensory neurons mediate inflammation induced by *Bacillus anthracis* Edema Toxin. *Frontiers in Immunology.* 2021 Aug 3;12:642373. doi:10.3389/fimmu.2021.642373. PMID: 34413846; PMCID: PMC8369925.  [PDF](/files/yang_et_al_2021_front_immunol_1.pdf)
5. Yang NJ, Isensee J, Neel D, Quadros AU, Zhang HXB, Lauzadis J, Liu SM, Shiers S, Belu Andreea, Palan S, Marlin S, Maignel J, Kennedy-Curran A, Tong VS, Moayeri M, Roderer P, Nitzsche A, Lu M, Pentelute BL, Brustle O, Tripathi V, Foster KA, Price TJ, Collier RJ, Leppla SH, Puopolo M, Cunha TM, Hucho T, **Chiu IM**. Anthrax toxins regulate pain signaling and can deliver molecular cargoes into Antxr2+ DRG sensory neurons. *Nature Neuroscience.* 2021 Dec 20. doi:10.1038/s41593-021-00973-8. Epub ahead of print. PMID: 34931070.  [PDF](/files/yang_et_al_2022_nat_neurosci_0.pdf)