Abstract
Human respiratory syncytial virus (RSV) is the leading cause of respiratory tract infections in humans. A well-known challenge in the development of a live attenuated RSV vaccine is that interferon (IFN)-mediated antiviral responses are strongly suppressed by RSV nonstructural proteins which, in turn, dampens the subsequent adaptive immune responses. Here, we discovered a novel strategy to enhance innate and adaptive immunity to RSV infection. Specifically, we found that recombinant RSVs deficient in viral RNA N6-methyladenosine (m6A) and RSV grown in m6A methyltransferase (METTL3)-knockdown cells induce higher expression of RIG-I, bind more efficiently to RIG-I, and enhance RIG-I ubiquitination and IRF3 phosphorylation compared to wild-type virion RNA, leading to enhanced type I IFN production. Importantly, these m6A-deficient RSV mutants also induce a stronger IFN response in vivo, are significantly attenuated, induce higher neutralizing antibody and T cell immune responses in mice and provide complete protection against RSV challenge in cotton rats. Collectively, our results demonstrate that inhibition of RSV RNA m6A methylation enhances innate immune responses which in turn promote adaptive immunity.
Highlights
Human respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in humans
We found that RSV RNA contains N6-methyladenosine (m6A) and that recombinant RSVs lacking m6A methylation induce significantly higher type I IFN in cell culture and in mice compared to the parental RSV
To begin to explore the role of viral m6A methylation in innate and adaptive immunity, we first generated RSV RNA that was naturally defective in m6A methylation using METTL3 knockdown (KD) U2OS cells
Summary
Human respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in humans. Worldwide it is estimated that RSV causes 3.4 million hospitalizations and between 66,000 and 199,000 deaths in young children less than 5 years of age [2,3]. In the 1960s, a formalin-inactivated (FI) RSV vaccine candidate was developed and tested in human clinical trials. This vaccine candidate failed to induce protection but led to an enhanced respiratory disease (ERD) upon RSV infection [4,5]. Many different RSV vaccine candidate types have been developed, including live attenuated, subunit, mRNA, virus-like particles, and viral vectored vaccines [6,7,8]. Live attenuated vaccines are one of the most promising candidates [6,7,9]
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