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Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses.

ABSTRACT: Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain-a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain. We highlight gaps in understanding of the mechanisms of acute and chronic COVID-19-associated cough and post-COVID syndrome, consider potential ways to reduce the effect of COVID-19 by controlling cough, and suggest future directions for research and clinical practice. Although neuromodulators such as gabapentin or opioids might be considered for acute and chronic COVID-19 cough, we discuss the possible mechanisms of COVID-19-associated cough and the promise of new anti-inflammatories or neuromodulators that might successfully target both the cough of COVID-19 and the post-COVID syndrome.

SUBMITTER: Song WJ

PROVIDER: S-EPMC8041436 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Neurotropic virus-based tracers have been extensively applied in mapping and manipulation of neural circuits. However, their neurotropic and neurotoxic properties remain to be fully characterized. METHODS:Through neural circuit tracing, we systematically compared the neurotropism discrepancy among different multi-trans-synaptic and mono-synaptic retrograde viral tracers including pseudorabies virus (PRV), rabies virus (RV), and the newly engineered retro adeno-associated virus (rAAV2-retro) tracers. The (single-cell) RNA sequencing analysis was utilized for seeking possible attribution to neurotropism discrepancy and comparing cell toxicity caused by viral infection between glycoprotein-deleted RV (RV-?G) and rAAV2-retro. Viral toxicity induced microglia activation and neuronal protein change were evaluated by immunohistochemistry. RESULTS:Multi-trans-synaptic retrograde viral tracers, PRV and RV, exhibit differential neurotropism when they were used for central neural circuit tracing from popliteal lymph nodes. Mono-synaptic retrograde tracers, including RV-?G and rAAV2-retro, displayed discrepant neurotropic property, when they were applied to trace the inputs of lateral hypothalamic area and medial preoptic nucleus. rAAV2-retro demonstrated preference in cerebral cortex, whereas RV-?G prefers to label basal ganglia and hypothalamus. Remarkably, we detected a distinct preference for specific cortical layer of rAAV2-retro in layer 5 and RV-?G in layer 6 when they were injected into dorsal lateral geniculate nucleus to label corticothalamic neurons in primary visual cortex. Complementation of TVA receptor gene in RV-resistant neurons enabled EnvA-pseudotyped RV infection, supporting receptors attribution to viral neurotropism. Furthermore, both RV-?G and rAAV2-retro exerted neurotoxic influence at the injection sites and retrogradely labeled sites, while the changes were more profound for RV-?G infection. Finally, we demonstrated a proof-of-concept strategy for more comprehensive high-order circuit tracing of a specific target nucleus by combining rAAV2-retro, RV, and rAAV tracers. CONCLUSIONS:Different multi-trans-synaptic and mono-synaptic retrograde viral tracers exhibited discrepant neurotropism within certain brain regions, even cortical layer preference. More neurotoxicity was observed under RV-?G infection as compared with rAAV2-retro. By combining rAAV2-retro, RV, and rAAV tracers, high-order circuit tracing can be achieved. Our findings provide important reference for appropriate application of viral tracers to delineate the landscape and dissect the function of neural network.

Project description:Many neurodegenerative and neurological diseases are rooted in dysfunction of the neuroimmune system; therefore, manipulating this system has strong therapeutic potential. Prior work has shown that exposing mice to flickering lights at 40 Hz drives gamma frequency (?40 Hz) neural activity and recruits microglia, the primary immune cells of the brain, revealing a novel method to manipulate the neuroimmune system. However, the biochemical signaling mechanisms between 40 Hz neural activity and immune recruitment remain unknown. Here, we exposed wild-type male mice to 5-60 min of 40 Hz or control flicker and assessed cytokine and phosphoprotein networks known to play a role in immune function. We found that 40 Hz flicker leads to increases in the expression of cytokines which promote microglial phagocytic states, such as IL-6 and IL-4, and increased expression of microglial chemokines, such as macrophage-colony-stimulating factor and monokine induced by interferon-?. Interestingly, cytokine effects differed as a function of stimulation frequency, revealing a range of neuroimmune effects of stimulation. To identify possible mechanisms underlying cytokine expression, we quantified the effect of the flicker on intracellular signaling pathways known to regulate cytokine levels. We found that a 40 Hz flicker upregulates phospho-signaling within the nuclear factor ?-light-chain-enhancer of activated B cells (NF-?B) and mitogen-activated protein kinase (MAPK) pathways. While cytokine expression increased after 1 h of 40 Hz flicker stimulation, protein phosphorylation in the NF-?B pathway was upregulated within minutes. Importantly, the cytokine expression profile induced by 40 Hz flicker was different from cytokine changes in response to acute neuroinflammation induced by lipopolysaccharides. These results are the first, to our knowledge, to show how visual stimulation rapidly induces critical neuroimmune signaling in healthy animals.SIGNIFICANCE STATEMENT Prior work has shown that exposing mice to lights flickering at 40 Hz induces neural spiking activity at 40 Hz (within the gamma frequency) and recruits microglia, the primary immune cells of the brain. However, the immediate effect of 40 Hz flicker on neuroimmune biochemical signaling was unknown. We found that 40 Hz flicker leads to significant increases in the expression of cytokines, key immune signals known to recruit microglia. Furthermore, we found that 40 Hz flicker rapidly changes the phosphorylation of proteins in the NF-?B and MAPK pathways, both known to regulate cytokine expression. Our findings are the first to delineate a specific rapid immune signaling response following 40 Hz visual stimulation, highlighting both the unique nature and therapeutic potential of this treatment.

Project description:Introduction Il est désormais admis que les « orteils COVID » sont associés à la pathogenèse du SARS-CoV-2. Les descriptions sont concordantes dans le monde entier, mais le suivi est peu décrit. Nous présentons 4 cas « d’orteils COVID » avec un suivi de plusieurs mois. Matériel et méthodes Entre février 2020 et avril 2021, 4 cas de plus de 3 mois ont été suivis rétrospectivement dans notre clinique dermatologique. Résultats Le premier patient était une femme de 19 ans sans antécédent médical. Deux mois après l’apparition des symptômes de la COVID-19, des lésions acrales de type engelures apparaissaient sur les orteils. Elle se plaignait de démangeaisons. Il n’y avait pas d’aggravation avec le froid. La sérologie SARS-CoV-2 était positive, et la recherche d’anticorps antinucléaires, de cryoglobuline, de cryofibrinogène, d’agglutinines froides était négative. Les engelures étaient encore visibles à 4 mois. Le deuxième patient était une femme de 18 ans en bonne santé. Deux semaines après l’apparition des signes de la COVID-19, des engelures asymptomatiques apparaissaient sur les orteils et les doigts. L’infection par le SARS-Cov-2 était confirmée par PCR nasopharyngée. En outre, on observait une éruption urticarienne transitoire et indolore du tronc, des genoux et des mains, exacerbée par la chaleur et disparaissant avec le froid. La biologie montrait des anticorps antinucléaires positifs avec une fluorescence nucléolaire, et un facteur rhumatoïde. Les engelures étaient encore visibles à 3 mois. Le troisième patient était une femme de 60 ans en bonne santé. Peu après les signes de la COVID-19 avec des symptômes typiques légers, apparaissaient des engelures indolores des orteils. Elle notait une exacerbation par la chaleur, mais pas d’aggravation par le froid. Un épisode de nécrose digitale fut observé et les engelures disparaissaient après cinq mois. Le 4e cas était une femme de 20 ans qui souffrait de symptômes compatibles avec la COVID-19. Cependant, aucune PCR nasopharyngée n’était réalisée et la sérologie était négative. Deux mois plus tard, des engelures et une érythromélalgie apparaissaient sur les orteils. Aucune autre cause n’était trouvée. Les symptômes persistaient après 10 mois, avec à certains endroits une évolution nécrotique superficielle. Discussion Notre petite série de cas montre une durée d’évolution des engelures de 3 à 10 mois. La symptomatologie varie de l’absence de douleur à l’incapacité fonctionnelle, avec parfois une évolution nécrotique. Nos données montrent une longue durée de ces symptômes. À ce jour, les « orteils COVID » n’ont pas été intégrés dans le concept de « long COVID » représentant les complications persistantes de la COVID-19 ; et aucun syndrome acral aigu pédiatrique n’a eu cette durée d’évolution. Nous suggérons de définir les orteils chroniques de la COVID-19 comme une entité distincte des formes aiguës survenant au cours de l’infection.

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Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses.

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