Abstract：
Postviral bacterial infections are a major health care challenge in coronavirus infections, including COVID-19; however, the coronavirus-specific mechanisms of increased host susceptibility to secondary infections remain unknown. In humans, coronaviruses, including SARS-CoV-2, infect lung immune cells, including alveolar macrophages, a phenotype poorly replicated in mouse models of SARS-CoV-2. To overcome this, we used a mouse model of native murine β-coronavirus that infects both immune and structural cells to investigate coronavirus-enhanced susceptibility to bacterial infections. Our data show that coronavirus infection impairs the host ability to clear invading bacterial pathogens and potentiates lung tissue damage in mice. Mechanistically, coronavirus limits the bacterial killing ability of macrophages by impairing lysosomal acidification and fusion with engulfed bacteria. In addition, coronavirus-induced lysosomal dysfunction promotes pyroptotic cell death and the release of IL-1β. Inhibition of cathepsin B decreased cell death and IL-1β release and promoted bacterial clearance in mice with postcoronavirus bacterial infection.
摘要：
病毒后细菌感染是冠状病毒感染的主要医疗保健挑战，包括COVID-19；然而，宿主对继发感染的易感性增加的冠状病毒特异性机制仍然未知.在人类中,冠状病毒,包括SARS-CoV-2，感染肺部免疫细胞，包括肺泡巨噬细胞,在SARS-CoV-2的小鼠模型中复制不良的表型。为了克服这一点，我们使用同时感染免疫细胞和结构细胞的天然鼠β-冠状病毒小鼠模型来研究冠状病毒增强对细菌感染的易感性.我们的数据表明，冠状病毒感染会损害宿主清除入侵的细菌病原体的能力，并增强小鼠的肺组织损伤。机械上,冠状病毒通过损害溶酶体酸化和与吞噬的细菌融合来限制巨噬细胞的细菌杀伤能力。此外,冠状病毒诱导的溶酶体功能障碍促进细胞凋亡和IL-1β的释放。抑制组织蛋白酶B可减少冠状病毒细菌感染后小鼠的细胞死亡和IL-1β释放，并促进细菌清除。
