Extraordinary GU-rich single-strand RNA identified from SARS coronavirus contributes an excessive innate immune response

Abstract

A dangerous cytokine storm occurs in the SARS involving in immune disorder, but many aspects of the pathogenetic mechanism remain obscure since its outbreak. To deeply reveal the interaction of host and SARS-CoV, based on the basic structural feature of pathogen-associated molecular pattern, we created a new bioinformatics method for searching potential pathogenic molecules and identified a set of SARS-CoV specific GU-rich ssRNA fragments with a high-density distribution in the genome. In vitro experiments, the result showed the representative SARS-CoV ssRNAs had powerful immunostimulatory activities to induce considerable level of pro-inflammatory cytokine TNF-a, IL-6 and IL-12 release via the TLR7 and TLR8, almost 2-fold higher than the strong stimulatory ssRNA40 that was found previously from other virus. Moreover, SARS-CoV ssRNA was able to cause acute lung injury in mice with a high mortality rate in vivo experiment. It suggests that SARS-CoV specific GU-rich ssRNA plays a very important role in the cytokine storm associated with a dysregulation of the innate immunity. This study not only presents new evidence about the immunopathologic damage caused by overactive inflammation during the SARS-CoV infection, but also provides a useful clue for a new therapeutic strategy.

Characterization of antiviral T cell responses during primary and secondary challenge of laboratory cats with feline infectious peritonitis virus (FIPV)

“…Virus-induced inhibitory macrophages reported for the mouse model for the SARS-CoV [37] were shown to contribute to reduced dendritic cell activation with subsequent delay of virus-specific T cell responses and disease onset. Other inappropriate innate responses included unregulated proinflammatory cytokine responses leading either to a cytokine storm as reported for the SARS CoV [38,39] or to an overstimulation of B cells [40] possibly leading to enhancing antibody responses as described for the classical wet form of FIP [1,41,42]. Similar to SARS, overexpression of inflammatory cytokines including IL-6 and tumor necrosis factor (TNF)-α with a reduced expression of IL-10 have also been reported to be associated with the development of FIP [42].…”

Associations between immune-suppressive and stimulating drugs and novel COVID-19—a systematic review of current evidence

“…The JAK family of enzymes are responsible for signal transduction and JAK inhibitors play a major role in inhibiting and blocking cytokine release that can contribute to growth of malignant cells in cancer. JAK inhibitors are used in the treatment of cancer and inflammatory diseases such as rheumatoid arthritis [43].…”

“…Current studies investigating COVID-19/ other coronavirus strains and IL-6. (continued) [43] Extraordinary GU-rich singlestrand RNA identified from SARS coronavirus contributes an excessive innate immune response. • A new strain of SARS-CoV (strain v2163) was characterised and it was highly lethal in 5-to 6-week-old BALB/c mice.…”

SARS coronavirus infections of the lower respiratory tract and their prevention

“…27 GU-rich ssRNAs from SARS virus activate TLR7 and TLR8 in mice and thereby induce high levels of proinflammatory cytokines including TNF-α, IL-6, and IL-12 leading to lethal acute lung injury. 28 Thus SARS virus has the capacity to exacerbate lung inflammation while at the same time inhibiting antiviral interferon responses.…”