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.
Highlights
A major focus of current research is the development of novel and more effective immune stimulants that can be used as adjuvants, in order to increase vaccine efficacy and safety [1]
IFN-α production was clearly increased in a dose-dependent manner in cells treated with Nucleic acid band 2 (NAB2) and the transfection reagent lipofectamine, whereas we did not observe any difference in IL-6 production in NAB2 and poly(I:C)treated cells (Figure 1A)
In this work we show that NAB2, a yeastderived double-stranded RNA (dsRNA) molecule that signals through Toll-like receptor 3 (TLR3) and Melanoma Differentiation-Associated protein 5 (MDA-5), is able to induce a stronger IFN-α production and innate immune cell activation compared to poly(I:C), both in the mouse and human systems
Summary
A major focus of current research is the development of novel and more effective immune stimulants that can be used as adjuvants, in order to increase vaccine efficacy and safety [1]. A class of molecules that were shown to be highly efficient adjuvants are the pathogen-associated molecular patterns (PAMPs) [2]. PAMPs comprise molecular structures, such as specific lipids moieties, nucleic acid structures and lipoproteins, that are highly conserved across a wide range of microorganisms, and whose recognition by immune cells can play a critical role in the early detection of invading pathogens. PAMPs can trigger a specific group of innate immune sensors, called pattern-recognition receptors (PRRs), which, upon stimulation, promote the initiation of the innate immune response and the development and coordination of the subsequent adaptive immune response [3]. Nucleic acid-sensing PRRs are triggered by specific DNA and RNA structures, and are of particular importance for the detection of viral infections [4]. The stimulation of nucleic acid sensors, through synthetic molecules or naturally occurring nucleic acids, is of a special interest for cancer therapy
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