Research

Neuronal sensing of bacteria in pain and host defense
Nociceptors are the peripheral sensory neurons that detect noxious/harmful stimuli and mediate pain. We have found that nociceptors directly sense bacterial pathogens including S. aureus and S. pyogenes to produce pain. Upon activation, nociceptors release neuropeptides from peripheral nerve terminals which signal to immune cells and epithelial cells to regulate host defenses. We are interested in identifying novel mechanisms by which bacterial pathogens produce pain and determining the role of nociceptors in regulating the immune response during infection. We found that nociceptor-immune signaling directs impacts macrophage and neutrophil responses at barrier sites, and this feeds into the ability of the host to clear bacterial pathogens including S. pyogenes, Group B Streptococcus and S. pneumoniae. We recently found that Bacillus anthracis derived edema toxin silences pain, and engineering bacterial toxins can lead to novel approaches to produce analgesics. In the meninges, the key barrier site of the brain, bacterial pathogens hijack pain and neuroimmune signaling to facilitate brain invasion by polarizing antimicrobial macrophage responses. 

1. Isaac M Chiu, Balthasar A Heesters, Nader Ghasemlou, Christian A Von Hehn, Fan Zhao, Johnathan Tran, Brian Wainger, Amanda Strominger, Sriya Muralidharan, Alexander R Horswill, Juliane Bubeck Wardenburg, Sun Wook Hwang, Michael C Carroll, and Clifford J Woolf. “Bacteria activate sensory neurons that modulate pain and inflammation.” Nature. 2013 501, 7465, Pp. 52-7.
2. Kimbria J Blake, Pankaj Baral, Tiphaine Voisin, Ashira Lubkin, Felipe Almeida Pinho-Ribeiro, Kelsey L Adams, David P Roberson, Yuxin C Ma, Michael Otto, Clifford J Woolf, Victor J Torres, and Isaac M Chiu. “Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314.” Nat Commun. 2018 Jan 9, 1, Pp. 37. 
3. Pankaj Baral, Benjamin D Umans, Lu Li, Antonia Wallrapp, Meghna Bist, Talia Kirschbaum, Yibing Wei, Yan Zhou, Vijay K Kuchroo, Patrick R Burkett, Bryan G Yipp, Stephen D Liberles, and Isaac M Chiu. “Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia.” Nat Med. 2018 Mar 24, 4, Pp. 417-426.
4. Felipe A Pinho-Ribeiro, Buket Baddal, Rianne Haarsma, Maghnus O'Seaghdha, Nicole J Yang, Kimbria J Blake, Makayla Portley, Waldiceu A Verri, James B Dale, Michael R Wessels, and Isaac M Chiu. “Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection.” Cell. 2018 May 173, 5, Pp. 1083-1097.e22.
5. Nicole J Yang, Jörg Isensee, Dylan V Neel, Andreza U Quadros, Han-Xiong Bear Zhang, Justas Lauzadis, Sai Man Liu, Stephanie Shiers, Andreea Belu, Shilpa Palan, Sandra Marlin, Jacquie Maignel, Angela Kennedy-Curran, Victoria S Tong, Mahtab Moayeri, Pascal Röderer, Anja Nitzsche, Mike Lu, Bradley L Pentelute, Oliver Brüstle, Vineeta Tripathi, Keith A Foster, Theodore J Price, John R Collier, Stephen H Leppla, Michelino Puopolo, Bruce P Bean, Thiago M Cunha, Tim Hucho, and Isaac M Chiu. “Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2⁺ DRG sensory neurons.” Nat Neurosci. 2022 Feb 25, 2, Pp. 168-179.
6. Felipe A Pinho-Ribeiro, Liwen Deng, Dylan V. Neel, Ozge Erdogan, Himanish Basu, Daping Yang, Samantha Choi, Alec J. Walker, Simone Carneiro-Nascimento, Kathleen He, Glendon Wu, Beth Stevens, Kelly S. Doran, Dan Levy, and Isaac M. Chiu.  “Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion.” Nature. 2023 March, 615, 7952, Pp. 472-481.

Neuroimmune crosstalk in gut barrier immunity
The gastrointestinal tract is one of the most densely innervated organs in the body. Nociceptors innervate the gut from both the vagal ganglia and dorsal root ganglia (DRG), mediating pain and other protective reflexes. In this gut-brain-axis, signals from the gut regulate pain and brain function. We recently found that neurons can directly sense human commensal microbes, and that they can regulate the immune and epithelial cell populations in the gut. We are particularly interested in defining how nociceptors sense microbes and regulate inflammation in the gut. Nociceptors crosstalk with gut epithelial cell-types including microfold (M) cells to defend against Salmonella infection. We found that nociceptors signal directly to intestinal goblet cells via a CGRP-RAMP1 axis to modulate mucus production, microbiome homeostasis and gut barrier protection. IWe are now interested in defining how distinct gut-innervating neuronal subsets crosstalk with immune cells at homeostasis and gastrointestinal disorders and the underlying molecular mechanisms.

1. Nissan Yissachar, Yan Zhou, Lloyd Ung, Nicole Y Lai, James F Mohan, Allen Ehrlicher, David A Weitz, Dennis L Kasper, Isaac M Chiu*, Diane Mathis*, and Christophe Benoist*. “An Intestinal Organ Culture System Uncovers a Role for the Nervous System in Microbe-Immune Crosstalk.” Cell. 2017 Mar 168, 6, Pp. 1135-1148.e12. *Corresponding authors.
2. Nicole Y Lai, Melissa A Musser, Felipe A Pinho-Ribeiro, Pankaj Baral, Amanda Jacobson, Pingchuan Ma, David E Potts, Zuojia Chen, Donggi Paik, Salima Soualhi, Yiqing Yan, Aditya Misra, Kaitlin Goldstein, Valentina N Lagomarsino, Anja Nordstrom, Kisha N Sivanathan, Antonia Wallrapp, Vijay K Kuchroo, Roni Nowarski, Michael N Starnbach, Hailian Shi, Neeraj K Surana, Dingding An, Chuan Wu, Jun R Huh, Meenakshi Rao, and Isaac M Chiu. “Gut-Innervating Nociceptor Neurons Regulate Peyer's Patch Microfold Cells and SFB Levels to Mediate Salmonella Host Defense.” Cell. 2020 Jan 180, 1, Pp. 33-49.e22.
3. Daping Yang, Amanda Jacobson, Kimberly A Meerschaert, Joseph Joy Sifakis, Meng Wu, Xi Chen, Tiandi Yang, Youlian Zhou, Praju Vikas Anekal, Rachel A Rucker, Deepika Sharma, Alexandra Sontheimer-Phelps, Glendon S Wu, Liwen Deng, Michael D Anderson, Samantha Choi, Dylan Neel, Nicole Lee, Dennis L Kasper, Bana Jabri, Jun R Huh, Malin Johansson, Jay R Thiagarajah, Samantha J Riesenfeld, and Isaac M Chiu. “Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection.” Cell. 2022 Oct 185, 22, Pp. 4190-4205.
4. Yangyang Zhu*, Kimberly A Meerschaert*, Silvia Galvan-Pena, Na-Ryum Bin, Daping Yang, Himanish Basu, Ryo Kawamoto, Amre Shalaby, Stephen D Liberles, Diane Mathis, Christophe Benoist*, and Isaac M Chiu*. “A chemogenetic screen reveals that Trpv1-expressing neurons control regulatory T cells in the gut.” Science. 2024 Aug 385, 6708, Pp. eadk1679. *First and Corresponding authors.

Neuronal crosstalk with microbes and immune cells in itch
Itch is an unpleasant sensation that evokes a desire to scratch. We are interested in understanding how sensory neurons interact with skin-resident microbes and immune cells to drive itch. Atopic dermatitis is a chronic skin disease characterized by itchy lesions. We recently found that the cysteinyl leukotriene LTC4 activates sensory neurons through its receptor Cysltr2, and that this drives itch in a mouse model of atopic dermatitis. 95% of atopic dermatitis lesions are colonized by Staphylococcus aureus, a major human pathogen that could drive neural activation and itch. We found that S. aureus directly activates pruriceptor sensory neurons via a secreted serine protease, V8, which activates protease-activated receptor 1 (PAR1) expressed on neurons, driving itch and scratch damage. We aim to define how S. aureus and other microbes could contribute to itch. We are also understanding how V8 induced itch could drive downstream innate and adaptive immunity that predisposes to allergies.

1. Tiphaine Voisin, Caroline Perner, Marie-Angele Messou, Stephanie Shiers, Saltanat Ualiyeva, Yoshihide Kanaoka, Theodore J Price, Caroline L Sokol, Lora G Bankova, Frank K Austen, and Isaac M Chiu. “The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch.” Proc Natl Acad Sci U S A. 2021 March 118, 13. *Corresponding authors. 
2. Liwen Deng, Flavia Costa, Kimbria J Blake, Samantha Choi, Arundhasa Chandrabalan, Muhammad Saad Yousuf, Stephanie Shiers, Daniel Dubreuil, Daniela Vega-Mendoza, Corinne Rolland, Celine Deraison, Tiphaine Voisin, Michelle D Bagood, Lucia Wesemann, Abigail M Frey, Joseph S Palumbo, Brian J Wainger, Richard L Gallo, Juan-Manuel Leyva-Castillo, Nathalie Vergnolle, Theodore J Price, Rithwik Ramachandran, Alexander R Horswill, and Isaac M Chiu. 11/22/2023. “S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis.” Cell. 2023 Nov 186, 24, Pp. 5375-5393.e25.

Role of gasdermins and innate immune mechanisms in neurodegeneration
We are interested in defining innate immune mechanisms of neurodegeneration. Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s Disease (AD), and Frontotemporal dementia (FTD) are fatal neurodegenerative diseases for which there are few treatments. We are investigating the role of Gasdermin proteins, which are pore-forming executioner molecules, in driving cell death and innate immune activation in the CNS. In particular, we are focused on the role of Gasdermin D (GSDMD) and Gasdermin E (GSDME) and determining whether they play a role in neuronal cell death as triggered by mutant neurodegeneration associated proteins including MAPT (tau) and C9ORF72 associated dipeptide repeat proteins (DPRs). Conversely, we are interested in whether these same pathways could be protective in the context of viral or bacterial infections of the CNS. It is possible that GSDMs are a double edged sword, where they protect the brain from infectious challenge, but conversely trigger cell death in neurodegenerative diseases.

1. Dylan V Neel*, Himanish Basu*, Georgia Gunner, Matthew D Bergstresser, Richard M Giadone, Haeji Chung, Rui Miao, Vicky Chou, Eliza Brody, Xin Jiang, Edward Lee, Michelle E Watts, Christine Marques, Aaron Held, Brian Wainger, Clotilde Lagier-Tourenne, Yong-Jie Zhang, Leonard Petrucelli, Tracey L Young-Pearse, Alice S Chen-Plotkin, Lee L Rubin, Judy Lieberman*, and Isaac M Chiu*. “Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.” Neuron. 2023 April 111, 8, Pp. 1222-1240.e9. *First and Corresponding authors.