Defective Viral Particles Produced in Mast Cells Can Effectively Fight Against Lethal Influenza A Virus

Abstract

Mast cells play an important role in the pathogenesis of highly pathogenic H5N1 avian influenza virus (H5N1-HPAIV) infection. Defective viral particles (DPs) can interfere with the replication of infectious viruses and stimulate the innate immune response of host cells. However, DPs arising from mast cells during HPAIV replication and their potent antiviral actions has not been reported. Here, we showed that the human mastocytoma cell line, HMC-1, allowed for the productive replication of the H5N1-HPAIV. Compared with alveolar cell line A549, DPs were propagated preferentially and abundantly in mast cells following IAV infection, which can be attributed to the wide existence of Argonaute 2 (AGO2) in HMC-1 cells. In addition, DPs generated in H5N1-infected cells could provide great therapeutic protection on mice to fight against various influenza A viruses, which included not only homologous H5N1-HPAIV, but also heterologous H1N1, H3N2, H7N2, and H9N2. Importantly, DPs generated in H5N1-infected HMC-1 cells could diminish viral virulence in vivo and in vitro by triggering a robust antiviral response through type II interferon signaling pathways. This study is the first to illustrate the arising of DPs in H5N1-HPAIV infected mast cells and explore their favorable ability to protect mice from influenza A viruses infection, which provides a novel insight and valuable information for the progress of new strategies to fight influenza A viruses infection, especially highly pathogenic avian influenza virus infection by focusing on the DPs generated in mast cells.

Antiviral Activity of Influenza A Virus Defective Interfering Particles against SARS-CoV-2 Replication In Vitro through Stimulation of Innate Immunity

“…Considering the emergence of new SARS-CoV-2 variants, against which a decreasing efficacy of various vaccines is becoming evident, the unspecific stimulation of innate immunity by IAV DIPs is considered advantageous; in particular, regarding a potential universal efficacy against such new (and future) variants. Furthermore, previous in vitro and in vivo experiments also revealed an antiviral effect of IAV DIPs against a variety of different IAV subtypes, including pandemic and highly pathogenic avian IAV strains [ 14 , 28 , 31 , 62 ].…”

Semi-continuous propagation of influenza A virus and its defective interfering particles: analyzing the dynamic competition to select candidates for antiviral therapy

“…One promising approach for antiviral therapy is the application of defective interfering particles (DIPs) (Dimmock and Easton, 2014; Huo et al, 2020; Vignuzzi and Lopez, 2019; Yang et al, 2019; Zhao et al, 2018). These naturally existing viral mutants feature an internal deletion in their viral genome, which renders them defective in virus replication.…”

“…Furthermore, interference was shown for the packaging step, as DI vRNAs selectively outcompeted FL vRNAs (Duhaut and McCauley, 1996; Odagiri and Tashiro, 1997). Notably, in mouse and ferret models, the administration of DIPs showed a pronounced antiviral effect against IAV (Dimmock et al, 2012; Dimmock et al, 2008; Hein et al, 2020; Huo et al, 2020; Zhao et al, 2018).…”

Antiviral activity of influenza A virus defective interfering particles against SARS-CoV-2 replicationin vitrothrough stimulation of innate immunity

“…Considering the emergence of new SARS-CoV-2 variants that render the efficacy of various vaccine candidates questionable, the unspecific stimulation of innate immunity by IAV DIPs may be advantageous; in particular, regarding a potential universal efficacy against such new (and future) variants. Furthermore, in vitro and in vivo experiments revealed an antiviral effect of IAV DIPs (derived from strains originally isolated in 1933 and 1934) against a variety of different IAV subtypes that have been isolated between 1933-2014, including pandemic and highly pathogenic avian IAV strains (Dimmock et al, 2008, Dimmock et al, 2012, Zhao et al, 2018, Huo et al, 2020a).…”

“…Furthermore, in vitro and in vivo experiments revealed an antiviral effect of IAV DIPs (derived from strains originally isolated in 1933 and 1934) against a variety of different IAV subtypes that have been isolated between 1933-2014, including pandemic and highly pathogenic avian IAV strains (Dimmock et al, 2008, Dimmock et al, 2012, Zhao et al, 2018, Huo et al, 2020a.…”