The coronavirus disease 2019 (COVID-19) pandemic has caused more than 6.3 million deaths to date. Despite great efforts to curb the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccines and neutralizing antibodies are in the gloom due to persistent viral mutations and antiviral compounds face challenges of specificity and safety. In addition, vaccines are unable to treat already-infected individuals, and antiviral drugs cannot be used prophylactically. Therefore, exploration of unconventional strategies to curb the current pandemic is highly urgent. Alveolar macrophages (AMs) residing on the surface of alveoli are the first immune cells that dispose of alveoli-invading viruses. Our findings demonstrate that M1 AMs have an acidic endosomal pH, thus favoring SARS-CoV-2 to leave endosomes and release into the cytosol where the virus initiates replication; in contrast, M2 AMs have an increased endosomal pH, which dampens the viral escape and facilitates delivery of the virus for lysosomal degradation. In this review, we propose that AMs are the Achilles’ heel of SARS-CoV-2 infection and that modulation of the endosomal pH of AMs has the potential to eliminate invaded SARS-CoV-2; the same strategy might also be suitable for other lethal respiratory viruses.

迄今为止，2019 年冠状病毒病 (COVID-19) 大流行已导致超过 630 万人死亡。尽管为遏制严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的传播做出了巨大努力，但由于持续的病毒突变和抗病毒化合物面临特异性和安全性的挑战，疫苗和中和抗体仍处于低迷状态。此外，疫苗无法治疗已经感染的个体，也无法预防性使用抗病毒药物。因此，探索非常规策略来遏制当前的大流行非常紧迫。位于肺泡表面的肺泡巨噬细胞 (AM) 是第一个处理侵入肺泡的病毒的免疫细胞。我们的研究结果表明 M1 AMs 具有酸性的内体 pH 值，因此有利于 SARS-CoV-2 离开内体并释放到病毒开始复制的细胞质中；相比之下，M2 AMs 具有增加的内体 pH 值，这会抑制病毒逃逸并促进病毒的传递以进行溶酶体降解。在这篇综述中，我们提出 AMs 是 SARS-CoV-2 感染的致命弱点，AMs 内体 pH 值的调节有可能消除入侵的 SARS-CoV-2；同样的策略也可能适用于其他致命的呼吸道病毒。我们提出，AMs 是 SARS-CoV-2 感染的致命弱点，AMs 内体 pH 值的调节有可能消除入侵的 SARS-CoV-2；同样的策略也可能适用于其他致命的呼吸道病毒。我们提出，AMs 是 SARS-CoV-2 感染的致命弱点，AMs 内体 pH 值的调节有可能消除入侵的 SARS-CoV-2；同样的策略也可能适用于其他致命的呼吸道病毒。