IFI16 directly senses viral RNA and enhances RIG-I transcription and activation to restrict influenza virus infection

Jiang, Zhimin; Wei, Fanhua; Zhang, Yuying; Wang, Tong; Gao, Weihua; Yu, Shufang; Sun, Honglei; Pu, Juan; Sun, Yipeng; Wang, Mingyang; Qi, Ting; Gao, Chengjiang; Chang, Kin-Chow; Liu, Jinhua

doi:10.1038/s41564-021-00907-x

“…IFI6 is one of the earliest identified IFN induced gene encoding the IFN-α -inducible protein 6 which has been shown to exert antiviral activity towards viruses by inhibiting the EGFR signaling pathway 26-29 . IFI16 gene encodes the Interferon Gamma Inducible Protein 16 which has been shown to be involved in the sensing of intracellular DNA and inducing death of virus infected cells 30-33 . IFI44 encodes the Interferon-Induced Protein 44 which is induced by Type 1 but not Type II IFNs and has been reported to suppress viral transcription 34,35 .…”

Section: Resultsmentioning

confidence: 99%

Myeloid cell interferon responses correlate with clearance of SARS-CoV-2

Singh

¹

,

Aladyeva

²

,

Das

³

et al. 2021

Preprint

View full text Add to dashboard Cite

The emergence of mutant SARS-CoV-2 strains associated with an increased risk of COVID-19-related death necessitates better understanding of the early viral dynamics, host responses and immunopathology. While studies have reported immune profiling using single cell RNA sequencing in terminal human COVID-19 patients, performing longitudinal immune cell dynamics in humans is challenging. Macaques are a suitable model of SARS-CoV-2 infection. We performed longitudinal single-cell RNA sequencing of bronchoalveolar lavage (BAL) cell suspensions from adult rhesus macaques infected with SARS-CoV-2 (n=6) to delineate the early dynamics of immune cells changes. The bronchoalveolar compartment exhibited dynamic changes in transcriptional landscape 3 days post- SARS-CoV-2-infection (3dpi) (peak viremia), relative to 14-17dpi (recovery phase) and pre-infection (baseline). We observed the accumulation of distinct populations of both macrophages and T-lymphocytes expressing strong interferon-driven inflammatory gene signature at 3dpi. Type I IFN response was highly induced in the plasmacytoid dendritic cells. The presence of a distinct HLADR+CD68+CD163+SIGLEC1+ macrophage population exhibiting higher angiotensin converting enzyme 2 (ACE2) expression was also observed. These macrophages were significantly recruited to the lungs of macaques at 3dpi and harbored SARS-CoV-2, while expressing a strong interferon-driven innate anti-viral gene signature. The accumulation of these responses correlated with decline in viremia and recovery. The recruitment of a myeloid cell-mediated Type I IFN response is associated with the rapid clearance of SARS-CoV-2 infection in macaques.

show abstract

“…We have demonstrated that IFI16 interacts with IAV genomic RNA and restricts viral infection. Recently an independent group reported that IFI16 binds with IAV viral RNA ( Jiang et al., 2021 ). In addition, we also demonstrated that upon interacting with the IAV genomic RNA, it induces IFI16-dependent programmed cell death to eliminate infected cells.…”

Section: Discussionmentioning

confidence: 99%

Innate immune sensing of influenza A viral RNA through IFI16 promotes pyroptotic cell death

Mishra

¹

,

Raj

²

,

Kumar

³

et al. 2022

View full text Add to dashboard Cite

Summary Programmed cell death pathways are triggered by various stresses or stimuli, including viral infections. The mechanism underlying the regulation of these pathways upon Influenza A virus (IAV) infection is not well characterized. We report that a cytosolic DNA sensor IFI16 is essential for the activation of programmed cell death pathways in IAV infected cells. We have identified that IFI16 functions as an RNA sensor for the influenza A virus by interacting with genomic RNA. The activation of IFI16 triggers the production of type I, III interferons, and also pro-inflammatory cytokines via the STING-TBK1 and Pro-caspase-1 signaling axis, thereby promoting cell death (apoptosis and pyroptosis in IAV infected cells). On the contrary, IFI16 knockdown cells showed reduced inflammatory responses and also prevented cell mortality during IAV infection. Collectively, these results demonstrate the pivotal role of IFI16-mediated IAV sensing and its essential role in activating programmed cell death pathways.

show abstract

“…IFI6 is one of the earliest identi ed IFN induced gene encoding the IFN-a -inducible protein 6 which has been shown to exert antiviral activity towards viruses by inhibiting the EGFR signaling pathway [26][27][28][29] . IFI16 gene encodes the Interferon Gamma Inducible Protein 16 which has been shown to be involved in the sensing of intracellular DNA and inducing death of virus infected cells [30][31][32][33] . IFI44 encodes the Interferon-Induced Protein 44 which is induced by Type 1 but not Type II IFNs and has been reported to suppress viral transcription 34,35 .…”

Section: Resultsmentioning

confidence: 99%

Myeloid cell interferon responses correlate with clearance of SARS-CoV-2

Singh¹,

Aladyeva²,

Das

³

et al. 2021

Preprint

View full text Add to dashboard Cite

The emergence of mutant SARS-CoV-2 strains associated with an increased risk of COVID-19-related death necessitates better understanding of the early viral dynamics, host responses and immunopathology. While studies have reported immune profiling using single cell RNA sequencing in terminal human COVID-19 patients, performing longitudinal immune cell dynamics in humans is challenging. Macaques are a suitable model of SARS-CoV-2 infection. We performed longitudinal single-cell RNA sequencing of bronchoalveolar lavage (BAL) cell suspensions from adult rhesus macaques infected with SARS-CoV-2 (n=6) to delineate the early dynamics of immune cells changes. The bronchoalveolar compartment exhibited dynamic changes in transcriptional landscape 3 days post- SARS-CoV-2-infection (3dpi) (peak viremia), relative to 14-17dpi (recovery phase) and pre-infection (baseline). We observed the accumulation of distinct populations of both macrophages and T-lymphocytes expressing strong interferon-driven inflammatory gene signature at 3dpi. Type I IFN response was highly induced in the plasmacytoid dendritic cells. The presence of a distinct HLADR+CD68+CD163+SIGLEC1+ macrophage population exhibiting higher angiotensin converting enzyme 2 (ACE2) expression was also observed. These macrophages were significantly recruited to the lungs of macaques at 3dpi and harbored SARS-CoV-2, while expressing a strong interferon-driven innate anti-viral gene signature. The accumulation of these responses correlated with decline in viremia and recovery. The recruitment of a myeloid cell-mediated Type I IFN response is associated with the rapid clearance of SARS-CoV-2 infection in macaques.

show abstract

IFI16 directly senses viral RNA and enhances RIG-I transcription and activation to restrict influenza virus infection

Cited by 79 publications

References 55 publications

Myeloid cell interferon responses correlate with clearance of SARS-CoV-2

Myeloid cell interferon responses correlate with clearance of SARS-CoV-2

Innate immune sensing of influenza A viral RNA through IFI16 promotes pyroptotic cell death

Myeloid cell interferon responses correlate with clearance of SARS-CoV-2

Contact Info

Product

Resources

About