Publications

2023
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, 186, 24, Pp. 5375-5393.e25.Abstract
Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.
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Ozge Erdogan, Benoit Michot, Jinya Xia, Lama Alabdulaaly, Pilar Yesares Rubi, Vivian Ha, Isaac M Chiu, and Jennifer L Gibbs. 10/30/2023. “Neuronal-immune axis alters pain and sensory afferent damage during dental pulp injury.” Pain.Abstract
Dental pulp tissue is densely innervated by afferent fibers of the trigeminal ganglion. When bacteria cause dental decay near the pulpal tissue, a strong neuronal and immune response occurs, creating pulpitis, which is associated with severe pain and pulp tissue damage. Neuroimmune interactions have the potential to modulate both the pain and pathological outcome of pulpitis. We first investigated the role of the neuropeptide calcitonin gene-related peptide (CGRP), released from peptidergic sensory afferents, in dental pain and immune responses by using Calca knockout (Calca-/-) and wild-type (Calca+/+) mice, in a model of pulpitis by creating a mechanical exposure of the dental pulp horn. We found that the neuropeptide CGRP, facilitated the recruitment of myeloid cells into the pulp while also increasing spontaneous pain-like behavior 20% to 25% at an early time point. Moreover, when we depleted neutrophils and monocytes, we found that there was 20% to 30% more sensory afferent loss and increased presence of bacteria in deeper parts of the tissue, whereas there was a significant reduction in mechanical pain response scores compared with the control group at a later time point. Overall, we showed that there is a crosstalk between peptidergic neurons and neutrophils in the pulp, modulating the pain and inflammatory outcomes of the disease.
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Ozge Erdogan, Jingya Xia, Isaac M Chiu, and Jennifer L Gibbs. 9/9/2023. “Dynamics of Innate Immune Response in Bacteria-Induced Mouse Model of Pulpitis.” J Endod.Abstract
INTRODUCTION: During pulpitis, as bacteria penetrate deeper into the dentin and pulp tissue, a pulpal innate immune response is initiated. However, the kinetics of the immune response, how this relates to bacterial infiltration during pulpitis and an understanding of the types of immune cells in the pulp is limited. METHODS: Dental pulp exposure in the molars of mice was used as an animal model of pulpitis. To investigate the kinetics of immune response, pulp tissue was collected from permanent molars at different time points after injury (baseline, day 1, and day 7). Flow cytometry analysis of CD45+ leukocytes, including macrophages, neutrophils monocytes, and T cells, was performed. 16S in situ hybridization captured bacterial invasion of the pulp, and immunohistochemistry for F4/80 investigated spatial and morphological changes of macrophages during pulpitis. Data were analyzed using two-way ANOVA with Tukey's multiple comparisons. RESULTS: Bacteria mostly remained close to the injury site, with some expansion towards noninjured pulp horns. We found that F4/80+ macrophages were the primary immune cell population in the healthy pulp. Upon injury, CD11b + Ly6Ghigh neutrophils and CD11b + Ly6GintLy6Cint monocytes constituted 70-90% of all immune populations up to 7 days after injury. Even though there was a slight increase in T cells at day 7, myeloid cells remained the main drivers of the immune response during the seven-day time period. CONCLUSIONS: As bacteria proliferate within the pulp chamber, innate immune cells, including macrophages, neutrophils, and monocytes, predominate as the major immune populations, with some signs of transitioning to an adaptive immune response.
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Daping Yang, Nicole Almanzar, and Isaac M Chiu. 6/19/2023. “The role of cellular and molecular neuroimmune crosstalk in gut immunity.” Cell Mol Immunol.Abstract
The gastrointestinal tract is densely innervated by the peripheral nervous system and populated by the immune system. These two systems critically coordinate the sensations of and adaptations to dietary, microbial, and damaging stimuli from the external and internal microenvironment during tissue homeostasis and inflammation. The brain receives and integrates ascending sensory signals from the gut and transduces descending signals back to the gut via autonomic neurons. Neurons regulate intestinal immune responses through the action of local axon reflexes or through neuronal circuits via the gut-brain axis. This neuroimmune crosstalk is critical for gut homeostatic maintenance and disease resolution. In this review, we discuss the roles of distinct types of gut-innervating neurons in the modulation of intestinal mucosal immunity. We will focus on the molecular mechanisms governing how different immune cells respond to neural signals in host defense and inflammation. We also discuss the therapeutic potential of strategies targeting neuroimmune crosstalk for intestinal diseases.
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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. 4/19/2023. “Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.” Neuron.Abstract
Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Knockout of GSDME in SOD1G93A ALS mice prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammation. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that may contribute to neurodegeneration.
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Na-Ryum Bin, Sara L Prescott, Nao Horio, Yandan Wang, Isaac M Chiu, and Stephen D Liberles. 3/23/2023. “An airway-to-brain sensory pathway mediates influenza-induced sickness.” Nature, 615, 7953, Pp. 660-667.Abstract
Pathogen infection causes a stereotyped state of sickness that involves neuronally orchestrated behavioural and physiological changes1,2. On infection, immune cells release a 'storm' of cytokines and other mediators, many of which are detected by neurons3,4; yet, the responding neural circuits and neuro-immune interaction mechanisms that evoke sickness behaviour during naturalistic infections remain unclear. Over-the-counter medications such as aspirin and ibuprofen are widely used to alleviate sickness and act by blocking prostaglandin E2 (PGE2) synthesis5. A leading model is that PGE2 crosses the blood-brain barrier and directly engages hypothalamic neurons2. Here, using genetic tools that broadly cover a peripheral sensory neuron atlas, we instead identified a small population of PGE2-detecting glossopharyngeal sensory neurons (petrosal GABRA1 neurons) that are essential for influenza-induced sickness behaviour in mice. Ablating petrosal GABRA1 neurons or targeted knockout of PGE2 receptor 3 (EP3) in these neurons eliminates influenza-induced decreases in food intake, water intake and mobility during early-stage infection and improves survival. Genetically guided anatomical mapping revealed that petrosal GABRA1 neurons project to mucosal regions of the nasopharynx with increased expression of cyclooxygenase-2 after infection, and also display a specific axonal targeting pattern in the brainstem. Together, these findings reveal a primary airway-to-brain sensory pathway that detects locally produced prostaglandins and mediates systemic sickness responses to respiratory virus infection.
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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. 3/1/2023. “Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion.” Nature .Abstract
The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2 . Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, afecting more than 2.5 million people a year3–5 . How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8+ nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specifc RAMP1 defciency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP–RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis.
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Michel Enamorado, Warakorn Kulalert, Seong-Ji Han, Indira Rao, Jérémie Delaleu, Verena M Link, Daniel Yong, Margery Smelkinson, Louis Gil, Saeko Nakajima, Jonathan L Linehan, Nicolas Bouladoux, Josette Wlaschin, Juraj Kabat, Olena Kamenyeva, Liwen Deng, Inta Gribonika, Alexander T Chesler, Isaac M Chiu, Claire E Le Pichon, and Yasmine Belkaid. 2/2/2023. “Immunity to the microbiota promotes sensory neuron regeneration.” Cell, 186, 3, Pp. 607-620.e17.Abstract
Tissue immunity and responses to injury depend on the coordinated action and communication among physiological systems. Here, we show that, upon injury, adaptive responses to the microbiota directly promote sensory neuron regeneration. At homeostasis, tissue-resident commensal-specific T cells colocalize with sensory nerve fibers within the dermis, express a transcriptional program associated with neuronal interaction and repair, and promote axon growth and local nerve regeneration following injury. Mechanistically, our data reveal that the cytokine interleukin-17A (IL-17A) released by commensal-specific Th17 cells upon injury directly signals to sensory neurons via IL-17 receptor A, the transcription of which is specifically upregulated in injured neurons. Collectively, our work reveals that in the context of tissue damage, preemptive immunity to the microbiota can rapidly bridge biological systems by directly promoting neuronal repair, while also identifying IL-17A as a major determinant of this fundamental process.
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2022
Larissa Staurengo-Ferrari, Liwen Deng, and Isaac M Chiu. 11/2022. “Interactions between nociceptor sensory neurons and microbial pathogens in pain.” Pain, 163, Suppl 1, Pp. S57-S68. PDF
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. 10/11/2022. “Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection.” Cell.Abstract
Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.
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Isaac M Chiu and Roland Liblau. 8/2022. “Editorial overview: Special section neuroimmunology: Neuroimmune interactions in health and disease.” Curr Opin Immunol, 77, Pp. 102232. PDF
Xinhong Chen, Sripriya Ravindra Kumar, Cameron D Adams, Daping Yang, Tongtong Wang, Damien A Wolfe, Cynthia M Arokiaraj, Victoria Ngo, Lillian J Campos, Jessica A Griffiths, Takako Ichiki, Sarkis K Mazmanian, Peregrine B Osborne, Janet R Keast, Cory T Miller, Andrew S Fox, Isaac M Chiu, and Viviana Gradinaru. 5/23/2022. “Engineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems.” Neuron.Abstract
Gene therapy offers great promise in addressing neuropathologies associated with the central and peripheral nervous systems (CNS and PNS). However, genetic access remains difficult, reflecting the critical need for the development of effective and non-invasive gene delivery vectors across species. To that end, we evolved adeno-associated virus serotype 9 (AAV9) capsid in mice and validated two capsids, AAV-MaCPNS1 and AAV-MaCPNS2, across rodent species (mice and rats) and non-human primate (NHP) species (marmosets and rhesus macaques). Intravenous administration of either AAV efficiently transduced the PNS in rodents and both the PNS and CNS in NHPs. Furthermore, we used AAV-MaCPNS1 in mice to systemically deliver the following: (1) the neuronal sensor jGCaMP8s to record calcium signal dynamics in nodose ganglia and (2) the neuronal actuator DREADD to dorsal root ganglia to mediate pain. This conclusively demonstrates the translatability of these two systemic AAVs across four species and their functional utility through proof-of-concept studies in mice.
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Dylan V Neel, Himanish Basu, Georgia Gunner, and Isaac M Chiu. 5/7/2022. “Catching a killer: Mechanisms of programmed cell death and immune activation in Amyotrophic Lateral Sclerosis.” Immunol Rev.Abstract
In the central nervous system (CNS), execution of programmed cell death (PCD) is crucial for proper neurodevelopment. However, aberrant activation of these pathways in adult CNS leads to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). How a cell dies is critical, as it can drive local immune activation and tissue damage. Classical apoptosis engages several mechanisms to evoke "immunologically silent" responses, whereas other forms of programmed death such as pyroptosis, necroptosis, and ferroptosis release molecules that can potentiate immune responses and inflammation. In ALS, a fatal neuromuscular disorder marked by progressive death of lower and upper motor neurons, several cell types in the CNS express machinery for multiple PCD pathways. The specific cell types engaging PCD, and ultimate mechanisms by which neuronal death occurs in ALS are not well defined. Here, we provide an overview of different PCD pathways implicated in ALS. We also examine immune activation in ALS and differentiate apoptosis from necrotic mechanisms based on downstream immunological consequences. Lastly, we highlight therapeutic strategies that target cell death pathways in the treatment of neurodegeneration and inflammation in ALS.
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Liwen Deng and Isaac M Chiu. 4/20/2022. “A neuropeptide regulates immunity across species.” Neuron, 110, 8, Pp. 1275-1277.Abstract
Communication between the nervous system and immune system is important for regulating immunity in health and disease. Yu et al. (2022) show that neuropeptide Y and its homolog NPF serve as a "language" to facilitate crosstalk between these two systems across species, enabling neurons to downregulate harmful immune responses.
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Antonia Wallrapp, Daping Yang, and Isaac M Chiu. 4/2022. “Enteric glial cells mediate gut immunity and repair.” Trends Neurosci, 45, 4, Pp. 251-253.Abstract
In the gut, coordinated cell interactions regulate tissue repair and immunity. How enteric glial cells (EGCs) mediate these processes remained elusive. In a recent paper, Progatzky et al. demonstrate that EGCs interact with immune and mesothelial cells under homeostasis and helminth infection, revealing an indispensable role of an interferon-γ (IFNγ)-EGC-CXCL10 axis in tissue repair.
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Swalpa Udit, Kimbria Blake, and Isaac M Chiu. 3/2022. “Somatosensory and autonomic neuronal regulation of the immune response.” Nat Rev Neurosci, 23, 3, Pp. 157-171.Abstract
Bidirectional communication between the peripheral nervous system (PNS) and the immune system is a crucial part of an effective but balanced mammalian response to invading pathogens, tissue damage and inflammatory stimuli. Here, we review how somatosensory and autonomic neurons regulate immune cellular responses at barrier tissues and in peripheral organs. Immune cells express receptors for neuronal mediators, including neuropeptides and neurotransmitters, allowing neurons to influence their function in acute and chronic inflammatory diseases. Distinct subsets of peripheral sensory, sympathetic, parasympathetic and enteric neurons are able to signal to innate and adaptive immune cells to modulate their cellular functions. In this Review, we highlight recent studies defining the molecular mechanisms by which neuroimmune signalling mediates tissue homeostasis and pathology. Understanding the neural circuitry that regulates immune responses can offer novel targets for the treatment of a wide array of diseases.
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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. 2/25/2022. “Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2+ DRG sensory neurons.” Nat Neurosci, 25, 2, Pp. 168-179.Abstract
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 or 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.
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Lars E Clark, Sarah A Clark, ChieYu Lin, Jianying Liu, Adrian Coscia, Katherine G Nabel, Pan Yang, Dylan V Neel, Hyo Lee, Vesna Brusic, Iryna Stryapunina, Kenneth S Plante, Asim A Ahmed, Flaminia Catteruccia, Tracy L Young-Pearse, Isaac M Chiu, Paula Montero Llopis, Scott C Weaver, and Jonathan Abraham. 2/2022. “VLDLR and ApoER2 are receptors for multiple alphaviruses.” Nature, 602, 7897, Pp. 475-480.Abstract
Alphaviruses, like many other arthropod-borne viruses, infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history. Entry into evolutionarily divergent host cells can be accomplished by recognition of different cellular receptors in different species, or by binding to receptors that are highly conserved across species. Although multiple alphavirus receptors have been described1-3, most are not shared among vertebrate and invertebrate hosts. Here we identify the very low-density lipoprotein receptor (VLDLR) as a receptor for the prototypic alphavirus Semliki forest virus. We show that the E2 and E1 glycoproteins (E2-E1) of Semliki forest virus, eastern equine encephalitis virus and Sindbis virus interact with the ligand-binding domains (LBDs) of VLDLR and apolipoprotein E receptor 2 (ApoER2), two closely related receptors. Ectopic expression of either protein facilitates cellular attachment, and internalization of virus-like particles, a VLDLR LBD-Fc fusion protein or a ligand-binding antagonist block Semliki forest virus E2-E1-mediated infection of human and mouse neurons in culture. The administration of a VLDLR LBD-Fc fusion protein has protective activity against rapidly fatal Semliki forest virus infection in mouse neonates. We further show that invertebrate receptor orthologues from mosquitoes and worms can serve as functional alphavirus receptors. We propose that the ability of some alphaviruses to infect a wide range of hosts is a result of their engagement of evolutionarily conserved lipoprotein receptors and contributes to their pathogenesis.
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2021
Nicole J Yang, Dylan V Neel, Liwen Deng, Michelle Heyang, Angela Kennedy-Curran, Victoria S Tong, Jin Mo Park, and Isaac M Chiu. 8/3/2021. “Nociceptive Sensory Neurons Mediate Inflammation Induced by Edema Toxin.” Front Immunol, 12, Pp. 642373.Abstract
Bacterial products are able to act on nociceptive neurons during pathogenic infection. Neurogenic inflammation is an active part of pain signaling and has recently been shown to impact host-pathogen defense. Bacillus anthracis Edema Toxin (ET) produces striking edema in peripheral tissues, but the cellular mechanisms involved in tissue swelling are not completely understood. Here, we find that nociceptive neurons play a role in ET-induced edema and inflammation in mice. Subcutaneous footpad infection of B. anthracis Sterne caused ET-dependent local mechanical allodynia, paw swelling and body weight gain. Subcutaneous administration of ET induced paw swelling and vascular leakage, the early phases of which were attenuated in the absence of Trpv1+ or Nav1.8+ nociceptive neurons. Nociceptive neurons express the anthrax toxin receptor ANTXR2, but this did not mediate ET-induced edema. ET induced local cytokine expression and neutrophil recruitment, which were dependent in part on Trpv1+ nociceptive neurons. Ablation of Trpv1+ or Nav1.8+ nociceptive neurons also attenuated early increases in paw swelling and body weight gain during live B. anthracis infection. Our findings indicate that nociceptive neurons play an active role in inflammation caused by B. anthracis and Edema Toxin to potentially influence bacterial pathogenesis.
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Tiffany Lin, Daisy Quellier, Jeffrey Lamb, Tiphaine Voisin, Pankaj Baral, Felix Bock, Alfrun Schönberg, Rossen Mirchev, Gerald Pier, Isaac Chiu, and Mihaela Gadjeva. 5/6/2021. “Pseudomonas aeruginosa-induced nociceptor activation increases susceptibility to infection.” PLoS Pathog, 17, 5, Pp. e1009557.Abstract
We report a rapid reduction in blink reflexes during in vivo ocular Pseudomonas aeruginosa infection, which is commonly attributed and indicative of functional neuronal damage. Sensory neurons derived in vitro from trigeminal ganglia (TG) were able to directly respond to P. aeruginosa but reacted significantly less to strains of P. aeruginosa that lacked virulence factors such as pili, flagella, or a type III secretion system. These observations led us to explore the impact of neurons on the host's susceptibility to P. aeruginosa keratitis. Mice were treated with Resiniferatoxin (RTX), a potent activator of Transient Receptor Potential Vanilloid 1 (TRPV1) channels, which significantly ablated corneal sensory neurons, exhibited delayed disease progression that was exemplified with decreased bacterial corneal burdens and altered neutrophil trafficking. Sensitization to disease was due to the increased frequencies of CGRP-induced ICAM-1+ neutrophils in the infected corneas and reduced neutrophil bactericidal activities. These data showed that sensory neurons regulate corneal neutrophil responses in a tissue-specific matter affecting disease progression during P. aeruginosa keratitis. Hence, therapeutic modalities that control nociception could beneficially impact anti-infective therapy.
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