Suppression of miR-155 attenuates lung cytokine storm induced by SARS-CoV-2 infection in human ACE2-transgenic mice

Abstract

Coronavirus disease 2019 (COVID-19) is a recent global pandemic. It is a deadly human viral disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with a high rate of infection, morbidity and mortality. Therefore, there is a great urgency to develop new therapies to control, treat and prevent this disease. Endogenous microRNAs (miRNAs, miRs) of the viral host are key molecules in preventing viral entry and replication, and building an antiviral cellular defense. Here, we have analyzed the role of miR-155, one of the most powerful drivers of host antiviral responses including immune and inflammatory responses, in the pathogenicity of SARS-CoV-2 infection. Subsequently, we have analyzed the potency of anti-miR-155 therapy in a COVID-19 mouse model (mice transgenic for human angiotensin I-converting enzyme 2 receptor (tg-mice hACE2)). We report for the first time that miR-155 expression is elevated in COVID-19 patients. Further, our data indicate that the viral load as well as miR-155 levels are higher in male relative to female patients. Moreover, we find that the delivery of anti-miR-155 to SARS-CoV-2-infected tg-mice hACE2 effectively suppresses miR-155 expression, and leads to improved survival and clinical scores. Importantly, anti-miR-155-treated tg-mice hACE2 infected with SARS-CoV-2 not only exhibit reduced levels of pro-inflammatory cytokines, but also have increased anti-viral and anti-inflammatory cytokine responses in the lungs. Thus, our study suggests anti-miR-155 as a novel therapy for mitigating the lung cytokine storm induced by SARS-CoV-2 infection.

miRNAs: The Key Regulator of COVID-19 Disease

“…Zhai et al [ 137 ] identified a Borna virus-encoded protein which is able to suppress the expression of miR-155, which is implicated in innate immune responses. The suppression of miR-155 showed to attenuate lung cytokine storm in mice infected with SARS-CoV-2 [ 138 , 139 ]; here, we suggest that miR-155 could be regulated by viral proteins as well. Along the same line, miR-146a, miR-21, and miR-142 were found in COVID-19 patients triggering the inflammatory machinery through activating MAPK and NF-Ƙb signaling [ 140 ].…”

Role of microRNAs in COVID-19 with implications for therapeutics

“…In mammalian cells, miR-136 binds to the 3′-UTR of RIG-I transcript and promotes IL-6 and IFNβ accumulation. Likewise, the expression levels of IL-6 and IL-8 were significantly increased by miR-21-3p, miR-21-5p and miR-155-5p [11] , [58] , [59] . On the other hand, miR-146a, miR-146b and miR-200c reduce the expression of IL-6, IL-8, and C-C motif chemokine ligand 5 (CCL5) [60] , [61] .…”

“…IL-1 is mostly secreted by activated macrophages, neutrophils, and epithelial cells, which enhance the production of T lymphocyte–derived cytokine and Th2 cell responses. miR-155 upregulates IL-1 signaling pathway, while in contrary miR-146a depletion leads to IL-1, IL-6 and TNFα overproduction [59] , [64] , [67] . Therefore, modulation of these miRNAs would be useful in the control of the immune response in severe COVID-19 patients.…”

Mechanisms contributing to adverse outcomes of COVID-19 in obesity

“…Transcriptome analysis of three different human cell lines infected with SARS-CoV2 showed induction of inflammation-linked miRNAs such as miR-155, which is correlated with several viral diseases and involved in pulmonary damage in ARDS [305]. Moreover, in SARS-CoV2-infected transgenic mice expressing human ACE2, anti-miR-155 downregulated expression of miR-155 and reduced levels of pro-inflammatory cytokines, and improved survival of experimental animals [306]. Li et al analyzed differential expression of miRs in blood of ten COVID-19 patients and four healthy controls and identified top ten upregulated miRNAs of which miR-16-2-3p was the most upregulated, and top ten downregulated miRNAs of which miR-627-5p was the most downregulated [307].…”