Pain is a major component of inflammation, but the role of pain-sensing nociceptor neurons in the regulating the inflammatory process is not well understood. It is increasingly clear that molecular and cellular interactions between the nervous system and immune system play important roles in development, homeostasis, and tissue inflammation. Nociceptor neurons are specialized to detect noxious/harmful stimuli and upon activation, transduce the sensation of pain. Nociceptor neurons densely innervate peripheral tissues including the skin, lungs, and gastrointestinal tract, tissues that are often exposed to pathogenic infection. Bacterial infection often produces significant pain. Our previous work demonstrated that S. aureus directly activates nociceptor neurons through release of N-formyl peptides and the pore-forming toxin ?emolysin, thereby producing pain. Upon activation, these nociceptor neurons release neuropeptides that are able to directly act on the immune system. Thus, like the immune system, the nervous system is able to directly detect and respond to pathogens. We hypothesize that nociceptor neurons may play an important and previously unappreciated role in host defense against pathogens. The goal of this study is to determine the contribution of nociceptor neurons and their neuropeptides in modulating the function of both innate and adaptive immune cells during bacterial host defense. We will utilize specific genetic and pharmacological tools to silence or activate nociceptor neuron activity with microbiological and immunological analyses to ascertain the significance of neuro-immune communication in host defense against S. aureus infection. These experiments will test the role of nociceptor neurons in the regulation of: 1) Neutrophil and monocyte mediated clearance of S. aureus and dendritic cell activation during infection. 2) T cell responses to S. aureus including priming in lymph nodes and effector function at the site of infection. These analyses will determine the role of nociceptor neurons in regulating immunity and inflammation, a relatively unexplored and potentially significant area of research. These studies have the potential to transform our understanding of host-pathogen interactions and of neuro-immune mechanisms in bacterial host defense.

Public Health Relevance

Pain is a major component of many bacterial infections, including those caused by Staphylococcus aureus. However, the biological significance of pain-sensing nociceptor neurons in regulation of bacterial host defense is not well understood. In this study, we will analyze the role of nociceptor neurons in directly communicating with the innate and adaptive immune system to modulate S. aureus host defense. These findings have important implications in our understanding of host-pathogen interactions and in the treatment of inflammation and bacterial infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
1K22AI114810-01
Application #
8805399
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Huntley, Clayton C
Project Start
2015-04-15
Project End
2017-03-31
Budget Start
2015-04-15
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$162,000
Indirect Cost
$12,000
Name
Harvard Medical School
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Baral, Pankaj; Umans, Benjamin D; Li, Lu et al. (2018) Nociceptor sensory neurons suppress neutrophil and ?? T cell responses in bacterial lung infections and lethal pneumonia. Nat Med 24:417-426
Blake, Kimbria J; Baral, Pankaj; Voisin, Tiphaine et al. (2018) Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314. Nat Commun 9:37
Chiu, Isaac M (2018) Infection, Pain, and Itch. Neurosci Bull 34:109-119
Yang, Nicole J; Chiu, Isaac M (2017) Bacterial Signaling to the Nervous System through Toxins and Metabolites. J Mol Biol 429:587-605
Pinho-Ribeiro, Felipe A; Verri Jr, Waldiceu A; Chiu, Isaac M (2017) Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation. Trends Immunol 38:5-19
Lai, N Y; Mills, K; Chiu, I M (2017) Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence. J Intern Med 282:5-23
Yissachar, Nissan; Zhou, Yan; Ung, Lloyd et al. (2017) An Intestinal Organ Culture System Uncovers a Role for the Nervous System in Microbe-Immune Crosstalk. Cell 168:1135-1148.e12
Baral, Pankaj; Mills, Kimbria; Pinho-Ribeiro, Felipe A et al. (2016) Pain and Itch: Beneficial or Harmful to Antimicrobial Defense? Cell Host Microbe 19:755-9
Chiu, Isaac M; Pinho-Ribeiro, Felipe A; Woolf, Clifford J (2016) Pain and infection: pathogen detection by nociceptors. Pain 157:1192-3
Ghasemlou, Nader; Chiu, Isaac M; Julien, Jean-Pierre et al. (2015) CD11b+Ly6G- myeloid cells mediate mechanical inflammatory pain hypersensitivity. Proc Natl Acad Sci U S A 112:E6808-17

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