Document text
Principal Investigator: Joyce Sooyeon Kim
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2023
Award: $69,500
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Activation of sensory nerves, in particular nociceptive C-fibers, is a feature of most respiratory
viruses. Evidence of such activation is found in the classical consequences of C-fiber activation
including sneezing, sore throat, coughing, and reflex secretions. As well as causing the troubling
symptoms of viral infection, the activation of these nerves allows viruses to escape the body and be
transmitted to other hosts, i.e. nociceptor activation amplifies viral spread in a community. In addition,
activation of airway vagal C-fibers can lead to strong reflex bronchoconstriction and excessive
secretions that likely contribute to the exacerbation of asthma particularly in children. Given the
relevance to human disease, surprisingly little is known about how virus infection induces C-fiber
activation and sensitization. In theory, viral infection leads to C-fiber activation by two general
mechanisms. The first is that viral infection of epithelial cells leads to the production of a mediator(s)
that stimulates the C-fiber terminals. The second is that the virus itself directly activates the nerves.
This second mechanism will likely be dependent on the specific virus type. This proposal focuses on
this second (direct) mechanism of activation as it relates to coronaviruses. I hypothesize that the
coronavirus spike protein interacts directly with C-fiber terminals in a manner that activates and
sensitizes the nociceptive C-fibers. My preliminary data, using three orthogonal approaches, support
the conclusion that the spike protein directly activates (evokes action potential discharge) about 40-
50% of vagal C-fibers in mouse airways. My first aim is to characterize the subtype of vagal C-fibers
that are activated by spike protein and also to assess whether the spike protein, short of overt
activation, leads to the sensitization of C-fiber terminals, i.e. renders them more sensitive to other
activating stimuli. My second aim focuses on the mechanism. I hypothesize that this interaction
involves the galactin-3 fold in the spike protein, and occurs independently of the spike protein
receptor ACE2 or toll-like receptors. Irrespective of the proximal binding target, I will address our
hypothesis that activation is secondary to the opening of TRPV1 and or TRPA1 channels. These aims
will be addressed using single cell RT-PCR analysis of mRNA expression in airway specific
nociceptive C-fibers, extracellular and patch-clamp electrophysiology, and 2-photon live imaging
techniques. The results of the studies are expected to provide insights into a novel mechanism of
coronavirus induced airway C-fiber activation.
Terms: <0-11 years old><2-photon><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><Action Potentials><Acute Nasopharyngitis><Address><Affinity><Airway infections><Airway mucosa><Alveolus><Angiotensin Receptor><Asthma><Binding><Bronchi><Bronchial Alveolus><Bronchial Asthma><Bronchial Constriction><Bronchoconstriction><C Fiber><COPD><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 S protein><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19 S protein><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><Cell Body><Cell Surface Glycoproteins><Cell membrane><Cells><Child><Child Youth><Children (0-21)><Chronic><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><CoV S protein><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><CoV-2><CoV2><Common Cold><Communities><Coronaviridae><Coronavirus><Coronavirus glycoprotein S><Coronavirus spike protein><Coughing><Cytoplasmic Membrane><Data><Disease><Disorder><Dorsal Root Ganglia><Dysfunction><Electrophysiology><Electrophysiology (science)><Embryo><Embryonic><Epithelial Cells><Fellowship><Functional disorder><Goals><Homolog of Drosophila TOLL><Imaging Procedures><Imaging Technics><Imaging Techniques><Individual><Infection><Ion Channel><Ionic Channels><Lead><Lung><Lung Respiratory System><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Mediating><Mediator><Membrane><Membrane Channels><Membrane Glycoproteins><Mice><Mice Mammals><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle East Respiratory coronavirus><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Molecular><Molecular Interaction><Murine><Mus><Nasal><Nasal Passages Nose><Nerve><Nerve Cells><Nerve Unit><Nervous System><Neural Cell><Neural Crest><Neurocyte><Neurologic Body System><Neurologic Organ System><Neurons><Neurophysiology / Electrophysiology><Nociception><Nociceptors><Nodose Ganglion><Nose><Oropharyngeal><Oropharynx><Oropharynxs><Pb element><Phenotype><Physiopathology><Plasma Membrane><Process><Production><Protein Subunits><Proteins><Pulmonary Body System><Pulmonary Organ System><RT-PCR><RTPCR><Receptor Protein><Reflex><Reflex action><Research Proposals><Respiratory Disease><Respiratory Infections><Respiratory Mucosa><Respiratory System><Respiratory System Disease><Respiratory System Disorder><Respiratory System, Nose, Nasal Passages><Respiratory Tract Infections><Respiratory Tracts><Respiratory tract structure><Reverse Transcriptase Polymerase Chain Reaction><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Secondary to><Sensory><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Sneezing><Sore Throat><Spinal><Spinal Column><Spinal Ganglia><Spine><Stimulus><Surface><Surface Glycoproteins><Symptoms><TLR protein><TLR4><TLR4 gene><TRPA channel><TRPA1 Channel><TRPV1><TRPV1 gene><Toll Homologue><Toll-Like Receptor Family Gene><Toll-like receptors><Trachea><Trachea Proper><Transmission><Vertebral column><Viral><Viral Diseases><Virus><Virus Diseases><Wuhan coronavirus><activated Protein C><afferent nerve><angiotensin converting enzyme 2><angiotensin converting enzyme II><asthma attack><asthma exacerbation><backbone><beta CoV><beta coronavirus><betaCoV><betacoronavirus><corona virus><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus S protein><coronavirus disease 2019 S protein><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><coronavirus spike glycoprotein><dorsal root ganglion><electrophysiological><exacerbation in asthma><exacerbation prone asthma><exacerbation prone asthmatic><extracellular><hCoV19><heavy metal Pb><heavy metal lead><human disease><insight><kids><mRNA Expression><membrane structure><nCoV2><neuronal><nociceptive><nociceptive neurons><novel><oral pharyngeal><pain-sensing neurons><pain-sensing sensory neurons><pain-sensing somatosensory neurons><patch clamp><pathophysiology><plasmalemma><pulmonary><receptor><respiratory><respiratory virus><reverse transcriptase PCR><sensory nerve><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome-CoV><theories><toll-like receptor 4><transient receptor potential ankyrin><transient receptor potential cation channel V1><transient receptor potential channel subfamily A><transmission process><two-photon><viral infection><virtual><virus infection><virus morphology><virus-induced disease><windpipe><youngster><β CoV><β coronavirus><βCoV>