IFN-Alpha1 antisense RNA represses human influenza A virus growth in a guinea pig system

[tetano]

Front Biosci (Landmark Ed). 2019 Mar 1;24:798-818.
IFN-Alpha1 antisense RNA represses human influenza A virus growth in a guinea pig system.

Sakamoto R¹, Jiang S¹, Tsukada Y², Tsujimoto H², Kimura T³.
Author information

Abstract

We reported a natural antisense (AS) long non-coding RNA as an important modulator of interferon-Alpha1 (IFNA1) mRNA levels. We showed that IFN-Alpha1 AS promotes IFNA1 mRNA stability by transient duplex formation and inhibition of miR-1270-induced mRNA decay. Here, we performed a proof-of-concept experiment to verify that the AS-mRNA regulatory axis exerts in vivo control of innate immunity. We established a model system for influenza virus infection using guinea pig, which encodes a functional MX1 gene for the type I IFN pathway. This system allowed us to investigate the effects of antisense oligoribonucleotides representing functional domains of guinea pig IFN-Alpha1 AS on gpIFNA1 mRNA levels and, consequently, on viral proliferation in the respiratory tract of influenza virus-infected animals. We demonstrated that pulmonary-administered asORNs inhibited the proliferation of the virus in the animals by modulating IFNA1 mRNA levels. These results indicate that, in light of the proposed actions, asORNs may modulate the level of IFNA1 mRNA in vivo, indicating that IFN-Alpha1 AS plays a pivotal role in determining the outcome of type I IFN responses.


PMID: 30844714

[tetano]

Front Biosci (Landmark Ed). 2019 Mar 1;24:790-797.
A guinea pig IFNA1 gene with antiviral activity against human influenza virus infection.

Jiang S¹, Sakamoto R¹, Kimura T².
Author information

Abstract

We previously reported a natural antisense (AS) RNA as an important modulator of human interferon-Alpha1 (IFNA1) mRNA levels. Here, we identified the guinea pig (Cavia porcellus) IFNA1 gene to enable a proof-of-concept experiment to be performed to confirm that the AS-mRNA regulatory axis exerts in vivo control over innate immunity. We selected a guinea pig model system for influenza virus infection because guinea pigs encode a functional Mx1 gene, an important anti-viral effector in the type I interferon pathway. We identified 15 guinea pig IFNA1 gene candidates upon bioinformatic analysis and selected the three candidates with the highest sequence homology to Homo sapiens, Mus musculus and Marmota himalayana IFNA1. The anti-viral activity of guinea pig IFN-Alpha1 protein against influenza virus A/Puerto Rico/8/34- or endomyocarditis virus-infection was then determined for the three gene candidates. We identified cpIFNA1 as the candidate with the highest sequence homologies and best anti-viral effects. cpIFNA1 will enable us to perform a proof-of-concept experiment to verify that IFN-Alpha1 AS increases cpIFNA1 mRNA levels, resulting in inhibition of influenza virus proliferation in vivo.


PMID: 30844713