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Knockdown of chERVs block TLR3-IL-1β dependent inflammatory response in chicken macrophages

ABSTRACT: Chicken endogenous retroviruses (chERVs) are remnants of ancient retroviral infections and can profoundly affect the host antiviral innate immune response, although the mechanisms by which these changes occur are largely unknown. To investigate the antiviral function of chERVs in ALV-J infection, we knocked down the expression of chERVs in HD11 cells using the CRISPR/Cas9 technique and then performed RNA-sequencing on wild-type and mutant macrophages. Under the presence of chERVs, macrophages response to viral infection through MARCO-TLR3-IL-1β dependent inflammatory response. Conversely, knowndown of chERVs increased the viral replication levels and attenuated the antiviral inflammatory response.

ORGANISM(S): Gallus gallus

PROVIDER: GSE270098 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:The SARS-CoV-2 spike protein mediates attachment of the virus to host cell receptor and fusion between the virus and cell membrane. The S1 subunit of the spike glycoprotein (S1 protein) contains the angiotensin converting enzyme 2 (ACE2) receptor binding domain. The SARS-CoV-2 variants of concern contain mutations in the S1 subunit. The spike protein is the primary target of neutralizing antibodies generated following infection and constitutes the viral component of mRNA based COVID-19 vaccines. Therefore, in this work we assessed the effect of exposure (24 hours) of 10 nM SARS-CoV-2 recombinant S1 protein on physiologically relevant human bronchial (bro) and alveolar (alv) lung mucosa models cultured at air-liquid interface (ALI) (n=6/experimental group). Corresponding sham exposed samples served as control. The bro-ALI model was developed using primary bronchial epithelial cells and the alv-ALI model using representative type II pneumocytes. Exposure of S1 protein induced the surface expression of ACE2, toll like receptor (TLR) 2, and TLR4 in both bro-ALI and alv-ALI models. Transcript expression analysis identified 117 (bro-ALI) and 97 (alv-ALI) differentially regulated genes (p< 0.01). Pathway analysis revealed enriched terms as specific as COVID-19, interferon (IFN) signaling, influenza, Corona virus, anti-viral response in the bro-ALI. Secreted levels of Interleukin (IL) 4 and IL12 were significantly (p<0.05; non-parametric) increased whereas IL6 decreased in the bro-ALI. In case of alv-ALI, enriched terms involving p53, APRIL, tight junction, integrin kinase, IL1 signaling were identified. These terms are associated with lung fibrosis. Further, significantly (p<0.05; non-parametric) increased levels of secreted pro-inflammatory cytokines IFNγ, IL1ꞵ, IL2, IL4, IL6, IL8, IL10, IL12, IL13, and tumor necrosis factor alpha were detected in alv-ALI. Altered levels of these cytokines are also associated with lung fibrotic response. Taken together, we observed a typical anti-viral response in the bronchial model whereas a pro-fibrotic response in the alveolar model. Therefore the bro-ALI and alv-ALI models may serve as an easy and robust platform for assessing the pathogenicity of variants of concern at different lung regions.

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Knockdown of chERVs block TLR3-IL-1β dependent inflammatory response in chicken macrophages

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