Lung-innervating nociceptor sensory neurons suppresses Ly6chi monocyte responses to promote pneumonic sepsis

PROJECT SUMMARY
Carbapenem-resistant Klebsiella pneumoniae (CRKP) causes Gram-negative lung infections and fatal
pneumonia-derived sepsis (or pneumonic sepsis) for which minimal treatment options are available.
Importantly, CRKP-mediated pneumonia and sepsis is associated with immune suppression, rapid
bacterial dissemination, and high mortality rate (20-40%) among the hospitalized patients. Host
targeted alternative therapeutic approaches are thus necessary for pneumonic sepsis. The respiratory
tract is densely innervated by nociceptor sensory neurons that mediate cough and bronchoconstriction
and release of neuropeptides in the lungs, including calcitonin gene-related peptide (CGRP). Further,
the released CGRP acts on its receptor complex (RAMP1/CALCRL) expressed in immune cells for
immunomodulation. However, it is yet unknown the role of nociceptor neurons and CGRP in host
defenses to Gram-negative pneumonia and pneumonic sepsis. Specifically, this research project will
address the following two key questions: 1) Do nociceptor neurons and their subsets play role to alter
the host CRKP clearance abilities and survival in pneumonic sepsis 2) Does neuropeptide signaling
involve in driving pneumonic sepsis? Using both ‘loss and gain of function’ neuronal manipulating
strategies in mice and using the nociceptor-targeted pharmacologic approach and neuropeptide- and
neuropeptide receptor-deficient mice, this study will determine the role of neuroimmune interactions in
pneumonic sepsis to address these questions. The preliminary in vivo and in vitro data demonstrate
the host deleterious effects of nociceptor neurons and the CGRP signaling pathway for the defense
against CRKP-induced pneumonic sepsis. Furthermore, the nociceptor-depleted mice showed higher
CRKP clearance abilities and recruitment of neutrophils and inflammatory monocytes (Ly6Chi) at
primary site of infection as compared to the control littermates. However, Ly6Chi monocytes were only
observed to be critical for controlling CRKP dissemination. The proposed studies are significant and
innovative because they identify neuroimmune crosstalk between nociceptors and innate immune cells
as a novel mechanism to promote sepsis at both cellular and whole animal levels. Targeting the nervous
system directly, or through downstream receptor signaling pathways in immune cells, will inform about
the host-based strategy as a treatment modality for lethal Gram-negative infection and pneumonic
sepsis.

Grant Number: 1R21AI186057-01A1
NIH Institute/Center: NIH
Principal Investigator: Pankaj Baral