Induction of Alternatively Activated Macrophages Enhances Pathogenesis during Severe Acute Respiratory Syndrome Coronavirus Infection

Abstract

e Infection with severe acute respiratory syndrome coronavirus (SARS-CoV) causes acute lung injury (ALI) that often leads to severe lung disease. A mouse model of acute SARS-CoV infection has been helpful in understanding the host response to infection; however, there are still unanswered questions concerning SARS-CoV pathogenesis. We have shown that STAT1 plays an important role in the severity of SARS-CoV pathogenesis and that it is independent of the role of STAT1 in interferon signaling. Mice lacking STAT1 have greater weight loss, severe lung pathology with pre-pulmonary-fibrosis-like lesions, and an altered immune response following infection with SARS-CoV. We hypothesized that STAT1 plays a role in the polarization of the immune response, specifically in macrophages, resulting in a worsened outcome. To test this, we created bone marrow chimeras and celltype-specific knockouts of STAT1 to identify which cell type(s) is critical to protection from severe lung disease after SARS-CoV infection. Bone marrow chimera experiments demonstrated that hematopoietic cells are responsible for the pathogenesis in STAT1 ؊/؊ mice, and because of an induction of alternatively activated (AA) macrophages after infection, we hypothesized that the AA macrophages were critical for disease severity. Mice with STAT1 in either monocytes and macrophages (LysM/STAT1) or ciliated lung epithelial cells (FoxJ1/STAT1) deleted were created. Following infection, LysM/STAT1 mice display severe lung pathology, while FoxJ1/STAT1 mice display normal lung pathology. We hypothesized that AA macrophages were responsible for this STAT1-dependent pathology and therefore created STAT1/STAT6 ؊/؊ double-knockout mice. STAT6 is essential for the development of AA macrophages. Infection of the double-knockout mice displayed a lack of lung disease and prefibrotic lesions, suggesting that AA macrophage production may be the cause of STAT1-dependent lung disease. We propose that the control of AA macrophages by STAT1 is critical to regulating immune pathologies and for protection from long-term progression to fibrotic lung disease in a mouse model of SARS-CoV infection.

Macrophages: Their role, activation and polarization in pulmonary diseases

“…In severe acute respiratory syndrome (SARS)-Cov infection, STAT dependent pathway of macrophage polarization insulates the host from development of chronic fibrotic lung disease. M2 macrophages are critical for this process (Page et al, 2012). In addition, mixed M1 and M2 macrophages are associated with severe respiratory syncytial virus (RSV) induced bronchiolitis (Shirey et al, 2010).…”

Pulmonary macrophages: key players in the innate defence of the airways

“…Work in murine macrophages has demonstrated that influenza infection can result in compromised pathogen clearance, acute inflammation and cell recruitment 31. Infection with the severe acute respiratory syndrome (SARS) coronavirus, the causal agent of SARS, results in a significant accumulation of enlarged M2 macrophages in the lung 32. Spike (S) protein, a major structural component of SARS, induces the conversion of B cells into cells that resemble macrophages, when displayed on recombinant baculovirus 33.…”

The role of mononuclear phagocytes in Ebola virus infection

“…Additionally, the concept of Mϕ activation status altering the host immune response has been explored in diseases such as diabetes, cancer, and atherosclerosis, where it has been shown that Mϕ populations are skewed to an M1 “pro‐inflammatory” state in diabetes, an M2 “anti‐inflammatory” state in the case of cancer, and both M1 and M2 populations in various aspects of atherosclerosis . A number of studies have also investigated the role of Mϕ polarization in the context of infections with bacterial, parasitic and viral pathogens . Viral pathogens such as HIV can modulate the status of macrophages to avoid the immune response or facilitate proliferation and dissemination, suggestive of the “evolutionary arms‐race” between host and virus .…”