Poster abstracts
Poster number 87 submitted by Taiwei Li
SARS-Cov2 Nsp14 induce the NF-κB activation and IL-8 expression during infection
Taiwei Li (The Graduate Program in Molecular, Cellular, and Developmental Biology MCDB), Helu Liu (Department of Medicine, Columbia University Medical Center), Adam Kenny (Department of Microbial Infection and Immunity, The Ohio State University College of Medicine ), Jacob Yount (Department of Microbial Infection and Immunity, The Ohio State University College of Medicine ), Jianwen Que (Department of Medicine, Columbia University Medical Center), Jian Zhu (Department of Pathology, The Ohio State University College of Medicine )
Abstract:
Previous studies showed that SARS-Cov2 infection could induce the NF-κB activation and increase proinflammatory cytokines such as TNF-α, IL-6, and IL-8. These SRAS-Cov2-triggered inflammatory responses in patients' lungs potentially develop acute respiratory distress syndrome (ARDS) and cause a life-threatening lung injury. However, the mechanism of this host-viral interaction and pathogenesis process is still not well-understood and could be the targets for SRAS-Cov2/ARDS treatment.
We examined whether the early-expressing non-structural protein (Nsp) 10, 14, and 16 could affect the host cell NF-κB or IRES-pathway at the beginning of SARS-Cov2 infection. This study found that the SARS-Cov2 Nsp14 could increase the NF-κB p65 expression and nuclear translocation to activate the NF-κB signalings. The exogenous Nsp14 could increase the NF-κB-downstream IL-6 and IL-8 mRNA expression in transfected HEK293T and A549 cells. During the SARS-Cov2 infection in HEK293T-ACE2 cells, the mRNA of Nsp14, IL6, and IL-8 mRNA significantly increased at post 24 h infection. Also, we observed the increase of IL-8 expression in the hyperplasia of lung tissue from SARS-Cov2/ARDS patients.
We identified the interaction of Nsp14 and IMPDH2 by co-IP assay. Moreover, the IMPDH2 inhibitors, Ribarvirn and mycophenolic acid (MPA) could inhibit the Nsp14 mediated NF-κB activation and IL-8 induction. This study found that SARS-Cov2 Nsp14 affects the host signaling pathway besides its RNA exonuclease and methylase function. These results suggested that SARS-Cov2 Nsp14 interacts with host IMPDH2 to increase the NF-κB signaling and induce IL-8 expression, causing the abnormal inflammatory response and pathogenesis for ARDS. The possible inhibitor targeting Nsp14 or IMPDH2 may become a potential anti-viral drug against the SARS-Cov2 infection.
Keywords: SARS-Cov2, NF-B , IL-8