Vaccinations are widely credited with reducing death rates from COVID-19, but the underlying host-viral mechanisms/interactions for morbidity and mortality of SARS-CoV-2 infection remain poorly understood. Acute respiratory distress syndrome (ARDS) describes the severe lung injury, which is pathologically associated with alveolar damage, inflammation, non-cardiogenic edema, and hyaline membrane formation. Because proteostatic pathways play central roles in cellular protection, immune modulation, protein degradation, and tissue repair, we examined the pathological features for the unfolded protein response (UPR) using the surrogate biomarker glucose-regulated protein 78 (GRP78) and co-receptor for SARS-CoV-2. At autopsy, immunostaining of COVID-19 lungs showed highly elevated expression of GRP78 in both pneumocytes and macrophages compared with that of non-COVID control lungs. GRP78 expression was detected in both SARS-CoV-2-infected and un-infected pneumocytes as determined by multiplexed immunostaining for nucleocapsid protein. In macrophages, immunohistochemical staining for GRP78 from deceased COVID-19 patients was increased but overlapped with GRP78 expression taken from surgical resections of non-COVID-19 controls. In contrast, the robust in situ GRP78 immunostaining of pneumocytes from COVID-19 autopsies exhibited no overlap and was independent of age, race/ethnicity, and gender compared with that from non-COVID-19 controls. Our findings bring new insights for stress-response pathways involving the proteostatic network implicated for host resilience and suggest that targeting of GRP78 expression with existing therapeutics might afford an alternative therapeutic strategy to modulate host-viral interactions during SARS-CoV-2 infections.

人们普遍认为疫苗接种可以降低 COVID-19 的死亡率，但对 SARS-CoV-2 感染发病率和死亡率的潜在宿主病毒机制/相互作用仍知之甚少。急性呼吸窘迫综合征（ARDS）描述了严重的肺损伤，其病理学上与肺泡损伤、炎症、非心源性水肿和透明膜形成有关。由于蛋白抑制途径在细胞保护、免疫调节、蛋白质降解和组织修复中发挥着核心作用，因此我们使用替代生物标志物葡萄糖调节蛋白 78 (GRP78) 和共受体检查了未折叠蛋白反应 (UPR) 的病理特征。 SARS-CoV-2。尸检时，与非 COVID-19 对照肺相比，COVID-19 肺的免疫染色显示，肺细胞和巨噬细胞中 GRP78 的表达均高度升高。通过核衣壳蛋白多重免疫染色测定，在 SARS-CoV-2 感染和未感染的肺细胞中均检测到 GRP78 表达。在巨噬细胞中，已故 COVID-19 患者的 GRP78 免疫组织化学染色有所增加，但与非 COVID-19 对照手术切除中的 GRP78 表达重叠。相比之下，与非 COVID-19 对照相比，对来自 COVID-19 尸检的肺细胞进行的强有力的原位 GRP78 免疫染色没有表现出重叠，并且与年龄、种族/族裔和性别无关。我们的研究结果为涉及与宿主恢复力相关的蛋白抑制网络的应激反应途径带来了新的见解，并表明用现有疗法靶向 GRP78 表达可能提供一种替代治疗策略，以在 SARS-CoV-2 感染期间调节宿主与病毒的相互作用。