Inflammasome activation in infected macrophages drives COVID-19 pathology

Abstract

Chronic COVID-19 is characterized by persistent viral RNA and sustained interferon (IFN) response which is recapitulated and required for pathology in SARS-CoV-2 infected MISTRG6-hACE2 humanized mice. As in the human disease, monocytes, and macrophages in SARS-CoV-2 infected MISTRG6-hACE2 are central to disease pathology. Here, we describe SARS-CoV-2 uptake in tissue resident human macrophages that is enhanced by virus specific antibodies. SARS-CoV-2 replicates in these human macrophages as evidenced by detection of double-stranded RNA, subgenomic viral RNA and expression of a virally encoded fluorescent reporter gene; and it is inhibited by Remdesivir, an inhibitor of viral replication. Although early IFN deficiency leads to enhanced disease, blocking either viral replication with Remdesivir or the downstream IFN stimulated cascade by injecting anti-IFNAR2 in vivo in the chronic stages of disease attenuates many aspects of the overactive immune-inflammatory response, especially the inflammatory macrophage response, and most consequentially, the chronic disease itself.

Activated interstitial macrophages are a predominant target of viral takeover and focus of inflammation in COVID-19 initiation in human lung

“…Our scRNA-seq and smFISH analyses indicate that SARS-CoV-2 can also infect alveolar macrophages, as previously surmised 21,23 . However, in contrast to activated interstitial macrophages, there is neither viral takeover of the host cell transcriptome nor cell-autonomous induction of a substantial inflammatory response.…”

“…This could be due to effective host control or destruction of the virus in alveolar macrophages, or to viral evasion of detection 61 in order to complete its replication cycle (see accompanying manuscript). As other studies have also identified the importance of macrophage infection to COVID-19 pathogenesis 21–23 , our results highlight the need in future COVID-19 studies to resolve the molecular subtype of lung macrophages infected, the extent of their viral takeover, and the specific host cell response, in evaluating the role of infected macrophages in the disease.…”

“…The central role in the model of infected interstitial macrophages in the transition of COVID-19 pneumonia to ARDS and cytokine storm implies that blocking their infection would prevent the most serious consequences of COVID-19. In this regard, our finding that therapeutically relevant mAbs do not neutralize SARS-CoV-2 Spike-mediated entry into purified lung macrophages, although they do block ACE2- and Fcγ-receptor-mediated entry into human blood monocytes 22 and bone-marrow derived macrophages in humanized mice 23 , has important medical implications. It suggests that SARS-CoV-2 enters lung resident macrophages by a different mechanism than is targeted by current COVID-19 entry inhibitors, which have been largely developed and evaluated based on SARS-CoV-2 Spike binding affinity to ACE2, the canonical receptor for AT2 cells, or neutralization activity assayed in ACE2-expressing cell lines.…”

“…These approaches provide a picture of COVID-19 pneumonia at unprecedented cellular and molecular resolution, and have suggested models of pathogenesis involving not only infection of the alveolar epithelium but also implicating alveolar capillaries, macrophages and other myeloid cells 18,19,[21][22][23] and production of various inflammatory cytokines and chemokines 15,19 . It remains unclear which cells are the direct virus targets in the human lung, and the nature of their virus-induced host response -in particular, the origin and sequence of molecular signals that initiate, sustain, and propagate the inflammatory cascade that leads to COVID-19 ARDS 4 .…”

The BNT162b2 mRNA SARS-CoV-2 vaccine induces transient afucosylated IgG1 in naive but not antigen-experienced vaccinees

“…Afucosylated IgG1 may support antigen presentation on antigen-presenting cells through FcγRIIIa, as well as inducing better T-helper and memory B cell responses, and subsequent booster responses (43)(44)(45). In support of this, we observed that early afucosylated anti-S IgG1 responses correlated significantly with anti-S IgG levels after the second dose in naive individuals (41).…”