Alveolar macrophages: Achilles' heel of SARS-CoV-2 infection

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.