BREAKING! Yale, Harvard & Rockefeller Study Discovers That SARS-COV-2 Is Able To Enter & Replicate In Human Host Macrophages,Triggering Inflammatory Cascade!
A new study by researchers from Yale University, Harvard University and Rockefeller University has found that the SARS-CoV-2 coronavirus is not only able to penetrate into the human host macrophages but also replicates in them while triggering an inflammatory cascade and interferon upregulation that often results in COVID-19 disease severity.
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 COVID-19 Research
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 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.
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
The SARS-CoV-2 coronavirus causes mild to severe infection in humans, and to date has infected over 234 million people globally and caused more than 4.78 million COVID-19 deaths and is wreaking havoc on the healthcare services worldwide along with causing huge economic damage.
Though majority of individuals infected with SARS-CoV-2 experience mild flu-like infection, around 10-20% of people suffer chronic infection. Scientists have indicated two persistent factors in severely infected individuals and individuals suffering from post-COVID syndrome (PCS). These factors are continual interferon (IFN) response and the presence of persistent viral RNA, even several months after recovering from acute symptoms.
Furthermore prevailing conditions, such as the chronic inflammatory state in macrophages, delayed antibody production, and systemic lymphopenia, could result in the development of pulmonary fibrosis. Histopathological and transcriptional analyses of lungs affected by COVID-19 confirm this.
The study team had successfully induced similar chronicity associated with SARS-CoV-2 infection in MISTRG6-hACE2 humanized mice. These mice experienced the presence of persistent viral RNA as well as sustained type I IFN response in the lungs for at least one month after inoculation of the virus.
Interestingly during this period, the study team found the presence of detectable viral titers, which significantly reduced over time. Similar to that of SARS-CoV-2 infection in humans, monocytes and macrophages were produced in SARS-CoV-2 infected MISTRG6-hACE2 mice. Proinflammatory cytokines interleukin (IL)-1β, IL-18, TNF-α, and IL-6 were primarily found in the infected lungs.
Although increased cytokine levels such as IL-1β, IL-18, and IL-6 have been correlated with severe COVID-19 disease, the study team believes that more research is required to elucidate the role of these cytokines in disease severity.
Furthermore it is also vital to understand the effects of persistent viral RNA and the IFN response in severe COVID-19 infection and PCS. This new study addressed the above-discussed research gaps.
The study team indicated that the ability of the MISTRG6-hACE2 model to recapitulate chronic COVID-19 disease had enabled them to study the fundamental mechanisms associated with disease progression.
This model is also critical to determine the efficacy of possible therapeutics targeted to manipulate the underlying mechanisms associated with severe COVID-19 infection.
The study team conducted in vivo experiments to characterize the function of viral RNA in the hyperinflammatory macrophage response. These results are in line with a previous study that also detected SARS-CoV-2 viral RNA in mononuclear phagocytes, which were characterized using scRNA-seq analysis of autopsied lungs of COVID-19 patients.
Previous studies had also reported that CD14hiCD16hi cells and alveolar macrophages were chiefly enriched with viral RNA. https://www.nature.com/articles/s41586-021-03570-8
The authors of this study however pointed out that these cells did not co-express the common viral entry factors, i.e., ACE2 and TMPRSS28. The mouse model indicated that viral uptake resulted in an anti-viral immune response, which was elevated in the presence of monoclonal antibodies.
However, this increase did not influence the pathological outcome when introduced early.
The study team reported that persistent viral RNA production and sustained IFN response are essential for pathogenesis in SARS-CoV-2 infected MISTRG6-hACE2. The mechanistic study of this model described that tissue-resident human macrophages take up the SARS-CoV-2 virus, and following which, a series of events occur for approximately two days. Finally, SARS-CoV-2 partially replicates in these macrophages and activates an inflammatory program.
Numerous past studies had shown that when dexamethasone treatment was stopped too early, at the peak of infection when the viral load was extremely high, the patient's condition declined rapidly. https://pubmed.ncbi.nlm.nih.gov/33758831/
Thereby, this study reveals that an early anti-viral immune response is essential for disease control. Interestingly, researchers had also found that persistent anti-viral responses could be pathogenic.
Importantly the primary role of IFNs in the early phase of the COVID-19 disease has been successfully elucidated via this model. The study team explained that therapeutically targeting chronic viral replication or the late IFN response lowered several aspects of the overactive immune-inflammatory response, such as the inflammatory macrophage response.
The study team also detected double-stranded RNA, subgenomic viral RNA, and also reported the expression of a virally encoded fluorescent reporter gene in human macrophages.
The study team also proposed that the combination of antivirals that inhibitor viral replication and anti-IFNAR2 antibodies could be an effective therapy for the treatment of chronic COVID-19.
The study findings shed light on alternative therapeutics by targeting viral RNA and sustained IFN response for treating patients who are suffering from severe SARS-CoV-2 infection.
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