An ATP-Binding Cassette Transporter Gene Links Innate and Adaptive Immune Responses

Abstract

Positive-strand RNA viruses and DNA viruses generate double-stranded RNA (dsRNA) during their replication processes and innate immune responses against viral infections are orchestrated by numerous interferon-stimulating genes, yet the detailed coordination of downstream signaling of anti-viral immune responses is not fully understood. Recent studies suggest 2-5- Oligoadenylate Synthetase 1 (OAS1) may have a protective role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections; however, the mechanism regulating OAS1 remains uninvestigated. Our aim is to understand the regulation of OAS1 and its modulation of RNaseL activity, as this has significant implications for responses to RNA viruses, including Vesicular stomatitis virus (VSV) and SARS-CoV-2. We explore the hypothesis that ABCF1 an ATP-binding cassette family member protein, a key regulator of innate immune responses and macrophage polarization and cytokine storm, play a role in regulating the antiviral responses and downstream dsRNA signaling revealed by measuring responses to the synthetic dsRNA analog termed poly (I:C). We utilize ABCF1 haplo-insufficient mice to discover that ABCF1 modulates the amplitude and frequency of VSV-specific Cytolytic T lymphocyte in anti-viral immune responses and suggests that innate immune responses underpin this process. To understand this mechanism, we describe that ABCF1 interacts with 2-5-oligoadenylate synthetase 1 (OAS1) which in turn modulates essential proteins that leads to the modulation of RNaseL activity via ABCE1. Furthermore, we find that ABCF1 also influences the production of interferon- (IFN-) and interferon-{beta} (IFN-{beta}) in bone marrow-derived macrophages. Overall,, we unexpectedly discovered that ABCF1 acts as a crucial link between innate and adaptive immunity, regulating the development of adaptive Cytolytic T lymphocyte responses and interacting with OAS1, a key regulator of innate immune responses against viral infections. Exploring pharmacological agents that target ABCE1 or ABCF1 may lead to the discovery of novel modalities for countering SARS CoV-2 and other viruses where OAS1 is a crucial innate immune response gene.