A macrophage is an important constituent of the human host innate immune system and it is a type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells.
Severe or 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.
The team discovered 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.
Though early IFN deficiency leads to enhanced disease, blocking either viral replication with suitable antivirals or the downstream IFN stimulated cascade by injecting anti-IFNAR2 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.
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2021.09.27.461948v1
… deepening….
Two hallmarks of COVID-19 in severely sick patients and Post-COVID syndrome (PCS) are a sustained interferon (IFN) response and persistent viral RNA which can be detected for months even after resolution of the acute symptoms3–11.
This chronicity is recapitulated in SARS-CoV-2 infected MISTRG6-hACE2 humanized mice by persistent viral RNA and sustained type I IFN response in lungs up to at least one month after viral inoculation by which time viral titers are detectable but significantly reduced (manuscript in revision)12.
As in the human disease, monocytes, and macrophages in SARS-CoV-2 infected MISTRG6-hACE2 are central to disease pathology and the main source of proinflammatory cytokines interleukin (IL)-1β, IL-18, TNF-α and IL-6 in infected lungs. Of these cytokines elevated in COVID-19 patients, IL-1β, IL-18 and IL-6 also correlated with disease severity4–10. Additional studies are required to fully evaluate the role of these cytokines and the implications of persistent viral RNA, and the IFN response in severe COVID-19 and PCS.
The ability of the MISTRG6-hACE2 model to recapitulate key aspects of COVID-19 has enabled us to both learn fundamental mechanisms of disease progression and test possible therapeutics to target these disease mechanisms. Here, we characterized the role of viral RNA in the hyperinflammatory macrophage response in vivo and showed that persistent viral RNA production and sustained IFN response is required for pathogenesis in SARS-CoV-2 infected MISTRG6-hACE2.
We further show that tissue resident human macrophages take up SARS-CoV-2. Replicating SARS-CoV-2 in these human macrophages initiates an inflammatory cascade that endows infected macrophages with a unique transcriptome and contributes to the downstream type I IFN response.
Blocking either viral replication or the downstream IFN response in vivo during the chronic phase of the disease attenuates many aspects of the overactive immune-inflammatory response, especially the inflammatory macrophage response, and most consequentially, the disease itself.
