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Ablation of Adar1 in myeloid cells imprints a global antiviral state in the lung and heightens early immunity against SARS-CoV-2 [scRNA-Seq]

ABSTRACT: Under normal homeostatic conditions, self double-stranded RNA (self-dsRNA) is modified by adenosine deaminase acting on RNA 1 (ADAR1) to prevent the induction of a type I interferon (IFN) mediated inflammatory cascade. Antigen presenting cells (APCs) sense pathogen associated molecular patterns (PAMPs), such as dsRNA, to activate the immune response. The impact of ADAR1 on the function of APCs and the consequences on immunity is poorly understood. Here, we show that ADAR1 deletion in CD11c+ APCs leads to: (i) a skewed myeloid cell compartment enriched in inflammatory cDC2s (inf-cDC2) like cells; (ii) enhanced numbers of activated tissue resident memory T cells (TRMs) in the lung; and (iii) the imprinting of a broad antiviral transcriptional signature across both immune and non-immune cells. Further the resulting changes can be partially reversed by blocking IFNAR1 signaling and promote early resistance against SARS-CoV-2 infection. Our study provides insight into the consequences of self-dsRNA sensing in APCs on the immune system in the context of viral challenge.

ORGANISM(S): Mus musculus

PROVIDER: GSE222487 | GEO | 2023/01/22

REPOSITORIES: GEO

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Ablation of Adar1 in myeloid cells imprints a global antiviral state in the lung and heightens early immunity against SARS-CoV-2 [RNA-Seq]

Project description:Under normal homeostatic conditions, self double-stranded RNA (self-dsRNA) is modified by adenosine deaminase acting on RNA 1 (ADAR1) to prevent the induction of a type I interferon (IFN) mediated inflammatory cascade. Antigen presenting cells (APCs) sense pathogen associated molecular patterns (PAMPs), such as dsRNA, to activate the immune response. The impact of ADAR1 on the function of APCs and the consequences on immunity is poorly understood. Here, we show that ADAR1 deletion in CD11c+ APCs leads to: (i) a skewed myeloid cell compartment enriched in inflammatory cDC2s (inf-cDC2) like cells; (ii) enhanced numbers of activated tissue resident memory T cells (TRMs) in the lung; and (iii) the imprinting of a broad antiviral transcriptional signature across both immune and non-immune cells. Further the resulting changes can be partially reversed by blocking IFNAR1 signaling and promote early resistance against SARS-CoV-2 infection. Our study provides insight into the consequences of self-dsRNA sensing in APCs on the immune system in the context of viral challenge.

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