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

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Programmed cell death pathways are crucial responses to cellular stress, including viral infections.
• The specific mechanisms regulating these pathways during Influenza A virus (IAV) infection remain incompletely understood.

Purpose of the Study:

• To elucidate the role of the cytosolic DNA sensor IFI16 in programmed cell death activation during IAV infection.
• To identify IFI16's function in sensing IAV and initiating downstream signaling cascades.

Main Methods:

• Investigated IFI16's interaction with IAV genomic RNA.
• Analyzed the activation of interferon and pro-inflammatory cytokine production via STING-TBK1 and Pro-caspase-1 signaling.
• Assessed cell death (apoptosis and pyroptosis) and inflammatory responses in IFI16-expressing and IFI16-knockdown cells upon IAV infection.

Main Results:

• IFI16 acts as an RNA sensor for IAV, interacting with its genomic RNA.
• IFI16 activation leads to the production of type I and III interferons and pro-inflammatory cytokines.
• This activation involves the STING-TBK1 and Pro-caspase-1 signaling axes, promoting apoptosis and pyroptosis.
• Conversely, IFI16 knockdown significantly reduced inflammatory responses and prevented cell mortality in IAV-infected cells.

Conclusions:

• IFI16 plays a pivotal role in sensing IAV infection.
• IFI16 is essential for activating programmed cell death pathways, including apoptosis and pyroptosis, in response to IAV.
• Targeting IFI16-mediated sensing offers a potential strategy to modulate inflammatory responses and cell death during IAV infection.