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


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.

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
JCI Insight ; 7(2)2022 01 25.
Article in English | MEDLINE | ID: covidwho-1575230


Acute respiratory distress syndrome (ARDS) is a life-threatening syndrome, constituted by respiratory failure and diffuse alveolar damage that results from dysregulated local and systemic immune activation, causing pulmonary vascular, parenchymal, and alveolar damage. SARS-CoV-2 infection has become the dominant cause of ARDS worldwide, and emerging evidence implicates neutrophils and their cytotoxic arsenal of effector functions as central drivers of immune-mediated lung injury in COVID-19 ARDS. However, key outstanding questions are whether COVID-19 drives a unique program of neutrophil activation or effector functions that contribute to the severe pathogenesis of this pandemic illness and whether this unique neutrophil response can be targeted to attenuate disease. Using a combination of high-dimensional single-cell analysis and ex vivo functional assays of neutrophils from patients with COVID-19 ARDS, compared with those with non-COVID ARDS (caused by bacterial pneumonia), we identified a functionally distinct landscape of neutrophil activation in COVID-19 ARDS that was intrinsically programmed during SARS-CoV-2 infection. Furthermore, neutrophils in COVID-19 ARDS were functionally primed to produce high amounts of neutrophil extracellular traps. Surprisingly, this unique pathological program of neutrophil priming escaped conventional therapy with dexamethasone, thereby revealing a promising target for adjunctive immunotherapy in severe COVID-19.

COVID-19/immunology , Extracellular Traps/immunology , Neutrophil Activation , Neutrophils/immunology , Respiratory Distress Syndrome/immunology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , COVID-19/pathology , Female , Humans , Male , Middle Aged , Neutrophils/pathology , Pneumonia, Bacterial/immunology , Pneumonia, Bacterial/pathology , Respiratory Distress Syndrome/pathology , Severity of Illness Index
Nat Med ; 28(1): 201-211, 2022 01.
Article in English | MEDLINE | ID: covidwho-1517637


Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during Coronavirus Disease 2019 (COVID-19) ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin signaling. Dexamethasone during severe COVID-19 affected circulating neutrophils, altered IFNactive neutrophils, downregulated interferon-stimulated genes and activated IL-1R2+ neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFNactive neutrophils and preferential steroid-induced immature neutrophil expansion, potentially affecting outcomes. Our single-cell atlas (see 'Data availability' section) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.

COVID-19/immunology , Cytokines/immunology , Dexamethasone/therapeutic use , Glucocorticoids/therapeutic use , Neutrophils/immunology , Pneumonia, Bacterial/immunology , Respiratory Distress Syndrome/immunology , Adult , Aged , COVID-19/complications , COVID-19/drug therapy , COVID-19/genetics , Cell Communication , Chromatography, Liquid , Down-Regulation , Female , Gene Regulatory Networks , Humans , Immunity, Innate/immunology , Interferons/immunology , Male , Middle Aged , Neutrophils/metabolism , Pneumonia, Bacterial/complications , Pneumonia, Bacterial/drug therapy , Pneumonia, Bacterial/genetics , Prostaglandins/immunology , Proteomics , RNA-Seq , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/genetics , SARS-CoV-2 , Severity of Illness Index , Sex Factors , Single-Cell Analysis , Tandem Mass Spectrometry