Length of dsRNA (poly I:C) drives distinct innate immune responses, depending on the cell type

Abstract

Poly I:C, a synthetic dsRNA analogue, has been used extensively for decades to study innate responses in vivo and in different cell types. We have found substantial variability while using poly I:C from different sources. In this study we found that poly I:C from 2 commercial sources induced sharply opposite responses in myeloid and fibroblasts, depending on the length of the poly I:C. Although short poly I:C (≈ 1-1.5 kb) induced greater amounts of TNF-α, IL-8, and IFN-β and a stronger antiviral response in myeloid cells, it was a poor inducer in fibroblasts. By contrast, long poly I:C (>5 kb) preferentially elicited higher cytokine and antiviral responses in fibroblasts and showed diminished responses in myeloid cells. Poly I:C activated NF-κB and STAT-1 signaling in a length- and cell-type-dependent fashion. Mechanistically, short poly I:C was better internalized in the myeloid cells and long poly I:C in the fibroblasts. Finally, long poly I:C required SR-A, whereas short poly I:C required RIG-I and Raftlin. We provide evidence that the length of dsRNA drives distinct innate responses in different cell lineages. These findings may augment in selecting the appropriate poly I:C type to design cell-type-specific potent adjuvants for vaccines against infectious diseases or cancers.

Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates

“…ii) Inconsistencies in immune-activating reagents – Despite the fact that PolyIC is a synthetic analog used to activate the maternal immune response in a controlled and temporally restricted manner, variations in production standards can have significant effects on its ability to drive an immune response. PolyIC consists of a chain of double stranded inosine (I) and cytidine (C) which can vary in length/molecular weight and demonstrate different immune activating properties in ex vivo paradigms (124, 125 ). Recent in vivo evaluation of PolyIC in a rat model confirms that the same dosage of high-molecular-weight PolyIC can elicit a cytokine response nearly a magnitude in degree higher when compared with low-molecular-weight PolyIC (126).…”

PrEP-001 prophylactic effect against rhinovirus and influenza virus - RESULTS of 2 randomized trials

“…PrEP-001, or Poly I:C, is a well-established synthetic doublestranded RNA that acts as a viral genome surrogate and activates the antiviral response of the cellular innate immune system by stimulating the PRRs Rig-1, MDA-5, and TLR3 (Caskey et al, 2011;Mian et al, 2013). It is a potent immunomodulating agent whose mechanism of action is well characterized (Wong et al, 1995).…”

“…Applied nasally, PrEP-001 or Poly I:C, is an effective immunomodulator currently in development for pan-viral prophylaxis against the common cold and influenza illness. Poly I:C is a well-established synthetic double-stranded RNA that acts as a viral genome surrogate and activates the antiviral response of the cellular innate immune system by stimulating the PRRs Rig-1, MDA-5, and TLR3 (Caskey et al, 2011;Mian et al, 2013).…”

Literature review of baseline information on non‐coding RNA (ncRNA) to support the risk assessment of ncRNA‐based genetically modified plants for food and feed

“…splenocytes, PBMCs, RAW264.7 and THP-1) (Mian et al, 2013). splenocytes, PBMCs, RAW264.7 and THP-1) (Mian et al, 2013).…”

“…Synthetic nucleic acids, such as dsRNAs, have been reported to be recognized by Toll-like receptor (TLR)-3 and can stimulate the innate immune system and trigger a Type I Interferon response (Marques et al, 2006;Mian et al, 2013). In plants, it has been described that dsRNA with 5' overhangs contributes to endogenous and antiviral RNA silencing pathways (Fukunaga and Doudna, 2009).…”