The Lung Macrophage in SARS-CoV-2 Infection: A Friend or a Foe?

Abstract

Respiratory, circulatory, and renal failure are among the gravest features of COVID-19 and are associated with a very high mortality rate. A common denominator of all affected organs is the expression of angiotensin-converting enzyme 2 (ACE2), a protease responsible for the conversion of Angiotensin 1-8 (Ang II) to Angiotensin 1-7 (Ang 1-7). Ang 1-7 acts on these tissues and in other target organs via Mas receptor (MasR), where it exerts beneficial effects, including vasodilation and suppression of inflammation and fibrosis, along an attenuation of cardiac and vascular remodeling. Unfortunately, ACE2 also serves as the binding receptor of SARS viral spike glycoprotein, enabling its attachment to host cells, with subsequent viral internalization and replication. Although numerous reports have linked the devastating organ injuries to viral homing and attachment to organ-specific cells widely expressing ACE2, little attention has been given to ACE-2 expressed by the immune system. Herein we outline potential adverse effects of SARS-CoV2 on macrophages and dendritic cells, key cells of the immune system expressing ACE2. Specifically, we propose a new hypothesis that, while macrophages play an important role in antiviral defense mechanisms, in the case of SARS-CoV, they may also serve as a Trojan horse, enabling viral anchoring specifically within the pulmonary parenchyma. It is tempting to assume that diverse expression of ACE2 in macrophages among individuals might govern the severity of SARS-CoV-2 infection. Moreover, reallocation of viral-containing macrophages migrating out of the lung to other tissues is theoretically plausible in the context of viral spread with the involvement of other organs.

Keywords: ACE2; SARS-CoV-2; acute respiratory distress syndrome; defense; lung; macrophages; reservoir.

Figure 1

Schematic structure of pulmonary alveoli with diverse cell types, including cuboid ciliated epithelial cells along bronchioles, alveolar type I (ATI) and type II epithelial cells (ATII), and macrophages. The latter are ubiquitous in the lungs and consist of two distinct populations: alveolar macrophages, which reside in proximity to ATI and ATII, as well as interstitial macrophages, which are abundant between the microvascular endothelium and alveolar epithelium zone. Alveolar macrophages as well as ATII express ACE2, the binding receptor of SARS-CoV-2. In addition, both cell types express TMPRSS2/Furin, which are also required for viral attachment. It exposes the viral receptor binding protein (RBP) localized to S-glycoprotein (S1 domain of the viral spike) and reveals the effusion site on the S2 domain. Although SARS-CoV-2 replication in ATII cells is well-documented, a similar process was not confirmed in alveolar macrophages. While some studies suggested such a replication along triggering aberrant production of proinflammatory cytokines/chemokines, as is the case with MERS-CoV, others reports ruled out SARS-CoV viral replication in human macrophages. ACE2, Angiotensin converting enzyme 2; ATI, Alveolar epithelial cells type I; ATII, Alveolar epithelial cells type II; TMPRSS2, Transmembrane protease, serine 2.