Immediate myeloid depot for SARS-CoV-2 in the human lung

Abstract

In the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, considerable focus has been placed on a model of viral entry into host epithelial populations, with a separate focus upon the responding immune system dysfunction that exacerbates or causes disease. We developed a precision-cut lung slice model to investigate very early host-viral pathogenesis and found that SARS-CoV-2 had a rapid and specific tropism for myeloid populations in the human lung. Infection of alveolar macrophages was partially dependent upon their expression of ACE2 and the infections were productive for amplifying virus, both findings which were in contrast with their neutralization of another pandemic virus, Influenza A virus (IAV). Compared to IAV, SARS-CoV-2 was extremely poor at inducing interferon-stimulated genes in infected myeloid cells, providing a window of opportunity for modest titers to amplify within these cells. Endotracheal aspirate samples from humans with COVID-19 confirmed the lung slice findings, revealing a persistent myeloid depot. In the early phase of SARS-CoV-2 infection, myeloid cells may provide a safe harbor for the virus with minimal immune stimulatory cues being generated, resulting in effective viral colonization and quenching of the immune system.

SARS-CoV-2 infection drives an inflammatory response in human adipose tissue through infection of adipocytes and macrophages

“…An important finding of our study is that adipocytes are not the only target of SARS-CoV-2 in adipose tissue, as we also detect SARS-CoV-2 RNA in a subset of inflammatory adipose tissue-resident macrophages. This finding is consistent with recent reports that SARS-CoV-2 can infect macrophages from the lung and secondary lymphoid organs, driving inflammatory pathology ( 38 , 99 – 104 ). In our study, we did not detect infectious virus release, suggesting abortive infection of adipose tissue macrophages.…”

“…In other tissues, whether macrophages can be productively infected remains debated. Two studies show productive infection of human alveolar macrophages and MDMs ( 103 , 104 ). However, numerous other studies report abortive infection of monocytes, macrophages, and MDM, hypothesizing that low ACE2 expression or pyroptosis prior to virus production and release lead to abortive infection ( 38 , 39 , 105 – 107 ).…”

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

“…These results are consistent with published scRNA sequencing analyses on ACE2 mRNA expression across cell types ( 20, 27–29 ). A recent preprint reported ACE2-positive macrophages in lung explants infected ex vivo , as determined by immunofluorescence ( 30 ). These data suggest that both ACE2-positive and ACE2-negative macrophages are present in SARS-CoV-2-infected lungs.…”

Macrophage ACE2 is necessary for SARS-CoV-2 replication and subsequent cytokine responses that restrict continued virion release

“…These results are consistent with published scRNA-seq analyses on ACE2 mRNA expression across cell types (20,(27)(28)(29). A preprint study reported the presence of ACE2-positive macrophages in lung explants infected ex vivo, as determined by immunofluorescence (30). These data suggest that both ACE2positive and ACE2-negative macrophages are present in SARS-CoV-2-infected lungs.…”