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1.
Front Immunol ; 12: 785355, 2021.
Article in English | MEDLINE | ID: covidwho-1594099

ABSTRACT

The lungs are constantly exposed to non-sterile air which carries harmful threats, such as particles and pathogens. Nonetheless, this organ is equipped with fast and efficient mechanisms to eliminate these threats from the airways as well as prevent pathogen invasion. The respiratory tract is densely innervated by sensory neurons, also known as nociceptors, which are responsible for the detection of external stimuli and initiation of physiological and immunological responses. Furthermore, expression of functional innate receptors by nociceptors have been reported; however, the influence of these receptors to the lung function and local immune response is poorly described. The COVID-19 pandemic has shown the importance of coordinated and competent pulmonary immunity for the prevention of pathogen spread as well as prevention of excessive tissue injury. New findings suggest that lung nociceptors can be a target of SARS-CoV-2 infection; what remains unclear is whether innate receptor trigger sensory neuron activation during SARS-CoV-2 infection and what is the relevance for the outcomes. Moreover, elderly individuals often present with respiratory, neurological and immunological dysfunction. Whether aging in the context of sensory nerve function and innate receptors contributes to the disorders of these systems is currently unknown. Here we discuss the expression of innate receptors by nociceptors, particularly in the lungs, and the possible impact of their activation on pulmonary immunity. We then demonstrate recent evidence that suggests lung sensory neurons as reservoirs for SARS-CoV-2 and possible viral recognition via innate receptors. Lastly, we explore the mechanisms by which lung nociceptors might contribute to disturbance in respiratory and immunological responses during the aging process.


Subject(s)
Aging/immunology , COVID-19/immunology , Immunity, Innate/immunology , Lung/immunology , Nociceptors/immunology , SARS-CoV-2/immunology , Transient Receptor Potential Channels/immunology , Aged , COVID-19/virology , Humans , Lung/innervation , Lung/virology , Nociceptors/metabolism , Nociceptors/virology , SARS-CoV-2/physiology , Sensory Receptor Cells/immunology , Sensory Receptor Cells/metabolism , Sensory Receptor Cells/virology , Transient Receptor Potential Channels/metabolism
2.
Front Immunol ; 12: 783725, 2021.
Article in English | MEDLINE | ID: covidwho-1554650

ABSTRACT

Interferons (IFNs) are cytokines that possess antiviral, antiproliferative, and immunomodulatory actions. IFN-α and IFN-ß are two major family members of type-I IFNs and are used to treat diseases, including hepatitis and multiple sclerosis. Emerging evidence suggests that type-I IFN receptors (IFNARs) are also expressed by microglia, astrocytes, and neurons in the central and peripheral nervous systems. Apart from canonical transcriptional regulations, IFN-α and IFN-ß can rapidly suppress neuronal activity and synaptic transmission via non-genomic regulation, leading to potent analgesia. IFN-γ is the only member of the type-II IFN family and induces central sensitization and microglia activation in persistent pain. We discuss how type-I and type-II IFNs regulate pain and infection via neuro-immune modulations, with special focus on neuroinflammation and neuro-glial interactions. We also highlight distinct roles of type-I IFNs in the peripheral and central nervous system. Insights into IFN signaling in nociceptors and their distinct actions in physiological vs. pathological and acute vs. chronic conditions will improve our treatments of pain after surgeries, traumas, and infections.


Subject(s)
Acute Pain/immunology , Chronic Pain/immunology , Interferon Type I/metabolism , Interferon-gamma/metabolism , /immunology , Acute Pain/pathology , Animals , Chronic Pain/pathology , Disease Models, Animal , Humans , Neuroglia/cytology , Neuroglia/immunology , Neuroglia/pathology , Nociceptors/immunology , Nociceptors/metabolism , Receptors, Interferon/metabolism , Signal Transduction/immunology , Spinal Cord/cytology , Spinal Cord/immunology , Spinal Cord/pathology
3.
Pain ; 161(11): 2494-2501, 2020 11.
Article in English | MEDLINE | ID: covidwho-878868

ABSTRACT

SARS-CoV-2 has created a global crisis. COVID-19, the disease caused by the virus, is characterized by pneumonia, respiratory distress, and hypercoagulation and can be fatal. An early sign of infection is loss of smell, taste, and chemesthesis-loss of chemical sensation. Other neurological effects of the disease have been described, but not explained. It is now apparent that many of these neurological effects (for instance joint pain and headache) can persist for at least months after infection, suggesting a sensory neuronal involvement in persistent disease. We show that human dorsal root ganglion (DRG) neurons express the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 at the RNA and protein level. We also demonstrate that SARS-CoV-2 and coronavirus-associated factors and receptors are broadly expressed in human DRG at the lumbar and thoracic level as assessed by bulk RNA sequencing. ACE2 mRNA is expressed by a subset of nociceptors that express MRGPRD mRNA, suggesting that SARS-CoV-2 may gain access to the nervous system through entry into neurons that form free nerve endings at the outermost layers of skin and luminal organs. Therefore, DRG sensory neurons are a potential target for SARS-CoV-2 invasion of the peripheral nervous system, and viral infection of human nociceptors may cause some of the persistent neurological effects seen in COVID-19.


Subject(s)
Betacoronavirus , Coronavirus Infections/metabolism , Ganglia, Spinal/metabolism , Nervous System Diseases/metabolism , Nociceptors/metabolism , Peptidyl-Dipeptidase A/biosynthesis , Pneumonia, Viral/metabolism , Spike Glycoprotein, Coronavirus/biosynthesis , Adult , Aged , Angiotensin-Converting Enzyme 2 , COVID-19 , Coronavirus Infections/genetics , Female , Ganglia, Spinal/virology , Gene Expression , Humans , Male , Middle Aged , Nervous System Diseases/genetics , Nervous System Diseases/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics
4.
Brain Behav Immun ; 89: 559-568, 2020 10.
Article in English | MEDLINE | ID: covidwho-457154

ABSTRACT

The SARS-CoV-2 virus infects cells of the airway and lungs in humans causing the disease COVID-19. This disease is characterized by cough, shortness of breath, and in severe cases causes pneumonia and acute respiratory distress syndrome (ARDS) which can be fatal. Bronchial alveolar lavage fluid (BALF) and plasma from mild and severe cases of COVID-19 have been profiled using protein measurements and bulk and single cell RNA sequencing. Onset of pneumonia and ARDS can be rapid in COVID-19, suggesting a potential neuronal involvement in pathology and mortality. We hypothesized that SARS-CoV-2 infection drives changes in immune cell-derived factors that then interact with receptors expressed by the sensory neuronal innervation of the lung to further promote important aspects of disease severity, including ARDS. We sought to quantify how immune cells might interact with sensory innervation of the lung in COVID-19 using published data from patients, existing RNA sequencing datasets from human dorsal root ganglion neurons and other sources, and a genome-wide ligand-receptor pair database curated for pharmacological interactions relevant for neuro-immune interactions. Our findings reveal a landscape of ligand-receptor interactions in the lung caused by SARS-CoV-2 viral infection and point to potential interventions to reduce the burden of neurogenic inflammation in COVID-19 pulmonary disease. In particular, our work highlights opportunities for clinical trials with existing or under development rheumatoid arthritis and other (e.g. CCL2, CCR5 or EGFR inhibitors) drugs to treat high risk or severe COVID-19 cases.


Subject(s)
Bronchoalveolar Lavage Fluid/immunology , Coronavirus Infections/immunology , Cytokines/immunology , Lung/immunology , Lung/innervation , Pneumonia, Viral/immunology , Receptors, Cytokine/immunology , Sensory Receptor Cells/immunology , Antirheumatic Agents/therapeutic use , Betacoronavirus , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Cytokines/metabolism , Databases, Factual , Ganglia, Spinal , Humans , Lung/metabolism , Lung/physiopathology , Molecular Targeted Therapy , Nociceptors/metabolism , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , RNA-Seq , Receptors, Cytokine/metabolism , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/physiopathology , SARS-CoV-2 , Sensory Receptor Cells/metabolism , Transcriptome , Up-Regulation
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