SARS-CoV-2 papain-like protease activates nociceptors to drive sneeze and pain.
SARS-CoV-2 papain-like protease activates nociceptors to drive sneeze and pain.
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SARS-CoV-2 木瓜蛋白酶样蛋白酶激活伤害感受器以引起打喷嚏和疼痛。
DOI：
10.1101/2024.01.10.575114
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Bautista,DianaM
中科院分区：
文献类型：
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作者：
Mali,SonaliS;Silva,Ricardo;Gong,Zhongyan;Cronce,Michael;Vo,Uyen;Vuong,Cliff;Moayedi,Yalda;Cox,JefferyS;Bautista,DianaM
SARS-CoV-2是导致COVID-19的病毒，可引发打喷嚏、疼痛和疼痛等症状。1这些症状由感觉神经元（称为伤害感受器）的子集介导，这些感觉神经元可检测有害刺激，密集地支配气道上皮，并与气道常驻上皮细胞和免疫细胞相互作用。2 -6然而，病毒感染激活这些神经元以触发疼痛和气道反射的机制尚不清楚。在这里，我们表明，冠状病毒木瓜蛋白酶样蛋白酶（PLpro）直接激活小鼠和人类iPSC衍生的伤害感受器中的气道神经支配的三叉神经和迷走神经伤害感受器。PLpro可诱发小鼠打喷嚏和急性疼痛，并触发气道传入神经肽降钙素基因相关肽（CGRP）的释放。我们发现PLpro诱导的喷嚏和疼痛需要宿主TRPA 1离子通道，该离子通道先前已被证明介导疼痛、咳嗽和气道炎症。7 -9我们的研究结果首次证明了一种病毒产物可直接激活感觉神经元以触发疼痛和气道反射，并强调了PLpro和伤害感受器在COVID-19中的新作用。
SARS-CoV-2, the virus responsible for COVID-19, triggers symptoms such as sneezing, aches and pain.1 These symptoms are mediated by a subset of sensory neurons, known as nociceptors, that detect noxious stimuli, densely innervate the airway epithelium, and interact with airway resident epithelial and immune cells.2–6 However, the mechanisms by which viral infection activates these neurons to trigger pain and airway reflexes are unknown. Here, we show that the coronavirus papain-like protease (PLpro) directly activates airway-innervating trigeminal and vagal nociceptors in mice and human iPSC-derived nociceptors. PLpro elicits sneezing and acute pain in mice and triggers the release of neuropeptide calcitonin gene-related peptide (CGRP) from airway afferents. We find that PLpro-induced sneeze and pain requires the host TRPA1 ion channel that has been previously demonstrated to mediate pain, cough, and airway inflammation.7–9 Our findings are the first demonstration of a viral product that directly activates sensory neurons to trigger pain and airway reflexes and highlight a new role for PLpro and nociceptors in COVID-19.