Macrophages only sense infectious SARS-CoV-2 when they express sufficient ACE2 to permit viral entry, where rapid cytokine responses then limit viral replication

Abstract

Macrophages are key cellular contributors to COVID-19 pathogenesis. Whether SARS-CoV-2 can enter macrophages, replicate and release new viral progeny remains controversial. Similarly, whether macrophages need to sense replicating virus to drive cytokine release is also unclear. Macrophages are heterogeneous cells poised to respond to their local microenvironment, and accordingly, the SARS-CoV-2 entry receptor ACE2 is only present on a subset of macrophages at sites of human infection. Here, we use in vitro approaches to investigate how SARS-CoV-2 interacts with ACE2-negative and ACE2-positive human macrophages and determine how these macrophage populations sense and respond to SARS-CoV-2. We show that SARS-CoV-2 does not replicate within ACE2-negative human macrophages and does not induce pro-inflammatory cytokine expression. By contrast, ACE2 expression in human macrophages permits SARS-CoV-2 entry, replication, and virion release. ACE2-expressing macrophages sense replicating virus to trigger pro-inflammatory and anti-viral programs that limit virus release. These combined findings resolve several controversies regarding macrophage-SARS-CoV-2 interactions and identify a signaling circuit by which macrophages sense SARS-CoV-2 cell entry and respond by restricting viral replication.

Stoking inflammasome fires in the COVID-19 neighborhood

“…SARS-CoV-2 can infect ACE2 (angiotensin I converting enzyme 2)-expressing airway epithelial cells (AEC), 3 monocytes 4 and macrophages. 5 Alternatively, antibodies promote SARS-CoV-2 uptake into monocytes independently of ACE2. 6 Cytosolic SARS-CoV-2 entry and active viral replication then activates inflammasome signaling in AECs and monocytes.…”

“…Myeloid cells are likely to be a primary source of elevated IL-1β in severe COVID-19, yet they are rarely directly infected by SARS-Cov-2 due to limited ACE2 expression. 5 Barnett et al. report no SARS-CoV-2 replication in peripheral blood mononuclear cells (PBMCs; containing lymphocytes [B, T, and NK cells; 70–90%], monocytes [10–20%], and dendritic cells [1–2%]), or mature IL-1β release from PBMCs, indicating that SARS-CoV-2 infection and cell-intrinsic inflammasome activation do not occur in monocytes or other leukocytes.…”