SARS-CoV-2 accessory proteins involvement in inflammatory and profibrotic processes through IL11 signaling

Abstract

SARS-CoV-2, the cause of the COVID-19 pandemic, possesses eleven accessory proteins encoded in its genome. Their roles during infection are still not completely understood. In this study, transcriptomics analysis revealed that both WNT5A and IL11 were significantly up-regulated in A549 cells expressing individual accessory proteins ORF6, ORF8, ORF9b or ORF9c from SARS-CoV-2 (Wuhan-Hu-1 isolate). IL11 is a member of the IL6 family of cytokines. IL11 signaling-related genes were also differentially expressed. Bioinformatics analysis disclosed that both WNT5A and IL11 were involved in pulmonary fibrosis idiopathic disease and functional assays confirmed their association with profibrotic cell responses. Subsequently, data comparison with lung cell lines infected with SARS-CoV-2 or lung biopsies from patients with COVID-19, evidenced altered profibrotic gene expression that matched those obtained in this study. Our results show ORF6, ORF8, ORF9b and ORF9c involvement in inflammatory and profibrotic responses. Thus, these accessory proteins could be targeted by new therapies against COVID-19 disease.

Effects of Combined Treatment with Sodium Dichloroacetate and Sodium Valproate on the Genes in Inflammation- and Immune-Related Pathways in T Lymphocytes from Patients with SARS-CoV-2 Infection with Pneumonia: Sex-Related Differences

“…IL11, a member of the IL6 cytokine family, is defined as an “epithelial interleukin”. High levels of IL11 are linked to prolonged inflammation [ 112 ]. IL23A is one of two subunits of cytokine IL23.…”

“…The increased BMP6 , CXCL8 and CXCL20 expressions are associated with anti-inflammatory effects. Whether the increase in IL11 levels is pathogenic or a natural host response to restore homeostasis in disease remains unanswered [ 112 ]. NODAL is important in controlling immunity and inflammation mechanisms, and its expression could be linked to female-specific immune responses.…”

Understanding interleukin 11 as a disease gene and therapeutic target

“…The scientific community working on lung fibrosis was quick to embrace the idea that IL11 is an important pro-fibrotic factor and a number of publications have validated and extended findings: 2020, IL11/ERK signalling is important for senescence of lung cells [ 68 ] and fibroblast-specific expression of IL11 causes lung fibro-inflammation [ 140 ]; 2021, IL11 expression is associated with lung fibrosis in patients with rheumatoid arthritis [ 153 ], replication of IL11 up-regulation and its effects in bleomycin injury and HPS [ 154 ]; 2022, nanoparticle delivery of siRNA against Il11 reduces lung fibrosis in the bleomycin mouse model [ 155 ], IL11 contributes to pulmonary artery remodelling and fibrosis in pulmonary hypertension [ 90 ], therapeutic targeting of IL11 reduces lung fibro-inflammation due to silica particle inhalation [ 156 ]; 2023, anti-IL11 reduces emphysematous disease in a mouse model of Marfan syndrome [ 157 ], IL11 disrupts alveolar epithelial cell repair functions by causing EMT [ 103 , 104 ], IL11 is elevated in interstitial lung disease in systemic sclerosis [ 158 , 159 ] and IL11 contributes to lung fibrosis in patients with SARS-COV-2 [ 160 , 161 ].…”

Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10

“…For instance, SOD activity might protect against SARS-CoV-2 induced oxidative stress 51 . Cardiovasculares) Viral Vector Unit (ViVU) as described previously 19,52 . Accessory proteins were C-terminally 2xStrep-tagged to check viral protein expression.…”

“…ORF9c interacts with Sigma receptors, implicated in lipid remodeling and stress responses in the endoplasmic reticulum 18 . Also, ORF9b and ORF9c have been involved in inflammatory and fibrotic processes via IL-11 19 .…”