NAB2 is a novel immune stimulator of MDA-5 that promotes a strong type I interferon response

Abstract

Novel adjuvants are needed to increase the efficacy of vaccine formulations and immune therapies for cancer and chronic infections. In particular, adjuvants that promote a strong type I IFN response are required, since this cytokine is crucial for the development of efficient anti-tumoral and anti-viral immunity. Nucleic acid band 2 (NAB2) is a double-stranded RNA molecule isolated from yeast and identified as an agonist of the pattern-recognition receptors TLR3 and MDA-5. We compared the ability of NAB2 to activate innate immunity with that of poly(I:C), a well-characterized TLR3 and MDA-5 agonist known for the induction of type I IFN. NAB2 promoted stronger IFN-α production and induced a higher activation state of both murine and human innate immune cells compared to poly(I:C). This correlated with a stronger activation of the signalling pathway downstream of MDA-5, and IFN-α induction was dependent on MDA-5. Upon injection, NAB2 induced higher levels of serum IFN-α in mice than poly(I:C). These results suggest that NAB2 has the potential to become an efficient adjuvant for the induction of type-I IFN responses in therapeutic immunization against cancer or infections.

Functional Interfaces, Biological Pathways, and Regulations of Interferon-Related DNA Damage Resistance Signature (IRDS) Genes

“…Therapeutic targeting IFIH1 or MDA5 gene is primary focused on identification of potent nucleic acid agonists, as MDA5 is one of a pivotal sensors of pathogen-associated molecular pattern (PAMP) and mediates downstream signalling to activate an antiviral and immunomodulatory response [ 127 ]. Recently, two high molecular weight dsRNA derived from natural sources have been reported; dsRNA (rb-dsRNA) corresponding to the genome of endornavirus extracted from rice bran [ 128 ] and nucleic acid band 2 (NAB2), a dsRNA corresponding to a yeast virus of the Totiviridiae family [ 129 ]. The specificity of RNA binding site in IFIT1 protein has been reported to be modulated by binding of another IRDS gene IFIT3.…”

Therapeutic Interventions Targeting Innate Immune Receptors: A Balancing Act

“…It is also under investigation for its ability to recruit immune cells in cancer, with preliminary evidence of efficacy alone and in combination with adaptive immunotherapies, such as anti-PD-L1 . Alongside such synthetic RNAs, a number of naturally occurring dsRNA structures have also shown efficacy in conferring in vivo protection that is at least partially dependent on MDA5, − and further structural studies on MDA5-PAMP interactions may inform more potent agonist design.…”

Harnessing the immune system to fight cancer with Toll-like receptor and RIG-I-like receptor agonists

“…The clinical success of TLR and RLR agonists is based on their capacity to efficiently mobilise both innate and adaptive immunity. Indeed, RNA-based compounds stimulating TLR7 or MDA-5 efficiently activate antitumoral CD8 + cytotoxic T cells 27,28 and promote strong type I interferon responses 29 . In addition to CD8 + T cells, NK cells play a pivotal role in anti-tumor immunity.…”