Research

 

Our goal is to understand the role of neural-immune interactions in pain, host defense, and immunity. It is increasingly clear that microbes and immune cells release mediators that impact the health and function of the nervous system. Neurons also release mediators that actively regulate innate and adaptive immune cell responses. We aim to define the molecular mechanisms defining how these cell-types communicate in health and disease.

                                                                          
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 are also interested in utilizing bacterial toxin engineering to treat pain. We recently found that Bacillus anthracis derived edema toxin silences pain. Engineering anthrax toxins can lead to novel approaches to produce analgesics that are selective for nociceptors. We are also studying neuro-immune crosstalk in host defense in both the skin and the respiratory tract.

  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.
  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.
  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.
  4. Baral P, Umans BD, Li Lu, Wallrapp A, Bist M, Kirschbaum T, Wei Y, Zhou Y, Kuchroo VK, Burkett PR, Yipp BG, Liberles SD, Chiu IM. Nociceptor sensory neurons suppress neutrophil and gd T cell responses in bacterial lung infections and lethal pneumonia. Nature Medicine. 2018 May;24(4):417-426.
  5. 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.
  6. 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.

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 (AD) 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 AD. 95% of AD lesions are colonized by Staphylococcus aureus, a major human pathogen that could drive neural activation and itch. We aim to define how S. aureus and other microbes could contribute to itch, and the role of neuroimmune signaling in AD.

                                                                                                

  1. Voisin T, Perner C, Messou MA, Shiers S, Kanaoka Y, Price TJ, Sokol CL, Bankova LG, Austen KF*, Chiu IM*. The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch. Proc. Natl. Acad. Sci. USA 2021 Mar 30;118(13)e2022087188.

Neuro-immune 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 are now interested in defining if distinct gut-innervating neuronal subsets play roles in regulating immune cells in gastrointestinal disorders including infection, ulcerative colitis and food allergies. Defining how neurons sense gut-derived signals and communicate with the gut could lead to new strategies to treat gastrointestinal diseases.

  1. Yissachar N, Zhou Y, Ung L, Lai NY, Mohan JF, Ehrlicher A, Weitz DA, Kasper D, Chiu IM*, Mathis D*, Benoist C*. An intestinal organ culture system uncovers a role for the nervous system in microbe/immunocyte crosstalk. Cell. 2017 Mar 9; 168(6):1135-1148.
  2. Lai NY, Musser MA*, Pinho-Ribeiro FA*, Baral P*, Jacobson A*, Ma P, Potts DE, Chen Z, Paik D, Soualhi S, Yan Y, Misra A, Goldstein K, Lagomarsino V, Nordstrom A, Sivanathan KN, Wallrapp A, Kuchroo VK, Nowarski R, Starnbach MN, Shi H, Surana NK, An D, Wu C, Huh JR, Rao M, Chiu IM. Gut-innervating nociceptor neurons regulate Peyer’s Patch Microfold cells and SFB levels to mediate Salmonella host defense. Cell. 2020 Jan 9;180(1)33-49.

Innate immune cell death mechanisms in neurodegeneration
We are interested in defining innate immune mechanisms of neurodegeneration. Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD) are fatal neurodegenerative diseases that lead to progressive loss of motor neurons and cortical neurons. We are investigating the role of Pyroptosis, a key inflammatory cell death pathway, in the CNS and how this could be dysregulated in neurodegeneration. We are also performing detailed characterization of how innate and adaptive immune cells are activated in mouse models of ALS/FTD. Defining how these innate immune cell death mechanisms are controlled in neurons and non-neuronal cells could lead to novel treatments for neurodegenerative diseases.

                                                              Mitochondria in neurons                                Neurons [magenta] co-cultured with microglia [cyan]