Person:

Chiu, Isaac

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Chiu

First Name

Isaac

Name

Chiu, Isaac

Filters

2021 - 20232

Settings

Author's Publications: search.filters.isAuthorOfPublication.b0989b31-7e2f-49b9-b8d2-97737d418729Start date: 2020

Search Results

Now showing 1 - 2 of 2
  • Thumbnail Image
    Publication

    Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion

    (Springer Science and Business Media LLC, 2023-03-01) Pinho-Ribeiro, Felipe A.; Deng, Liwen; Neel, Dylan V.; Erdogan, Ozge; Basu, Himanish; Yang, Daping; Choi, Samantha; Walker, Alec J.; Carneiro-Nascimento, Simone; He, Kathleen; Wu, Glendon; Stevens, Beth; Doran, Kelly S.; Levy, Dan; Chiu, Isaac

    The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2. How pain and neuroimmune interactions impact meningeal host defense is unclear. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system (CNS), affecting over 2.5 million people a year3-5. Here we find that Nav1.8+ neuron signaling to immune cells in the meninges via the neuropeptide calcitonin gene-related peptide (CGRP) exacerbates bacterial meningitis. Nociceptor ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors via Pneumolysin to release CGRP, which acts through its receptor RAMP1 on meningeal macrophages to inhibit chemokine expression, neutrophil recruitment and antimicrobial defenses. Macrophage-specific RAMP1 deficiency or blockade of RAMP1 signaling enhanced immune responses and bacterial clearance in meninges and brain. Therefore, targeting a neuro-immune axis in the meninges can enhance host defenses and potentially produce treatments for bacterial meningitis.

  • Thumbnail Image
    Publication

    Anthrax Toxins Regulate Pain Signaling and Can Deliver Molecular Cargoes Into ANTXR2+ DRG Sensory Neurons

    (Springer Science and Business Media LLC, 2021-12-20) Yang, Nicole J.; Isensee, Jörg; Neel, Dylan V.; Quadros, Andreza U.; Zhang, Han-Xiong Bear; Lauzadis, Justas; Liu, Sai Man; Shiers, Stephanie; Belu, Andreea; Palan, Shilpa; Marlin, Sandra; Maignel, Jacquie; Kennedy-Curran, Angela; Tong, Victoria S.; Moayeri, Mahtab; Röderer, Pascal; Nitzsche, Anja; Lu, Mike; Pentelute, Bradley L.; Brüstle, Oliver; Tripathi, Vineeta; Foster, Keith A.; Price, Theodore J.; Collier, Robert; Leppla, Stephen H.; Puopolo, Michelino; Bean, Bruce; Cunha, Thiago M.; Hucho, Tim; Chiu, Isaac

    Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF). Intrathecal administration of edema toxin (ET); (PA + EF) targeted DRG neurons and induced analgesia in mice. ET inhibited mechanical and thermal sensation, and pain caused by formalin, carrageenan and nerve injury. Analgesia depended on ANTXR2 expressed by Nav1.8+ or Advillin+ neurons. ET modulated protein kinase A signaling in mouse sensory and human induced pluripotent stem cell-derived sensory neurons, and attenuated spinal cord neurotransmission. We further engineered anthrax toxins to introduce exogenous protein cargoes, including botulinum toxin, into DRG neurons to silence pain. Our study highlights interactions between a bacterial toxin and nociceptors, which may lead to the development of new pain therapeutics.