Irf7 Deficiency Confers Protection Against Influenza Infection, Independent of irf3

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Interferon regulatory factors (IRF3 and IRF7) are crucial for antiviral immunity.
• Their specific roles in macrophages and dendritic cells (DCs) are not fully understood.

Purpose of the Study:

• To investigate the cell-type-specific functions of IRF3 and IRF7 in antiviral immunity.
• To elucidate their distinct contributions to macrophage and DC responses during influenza A virus (IAV) infection.

Main Methods:

• Multi-omics approach including in vitro assays, in vivo IAV infection models, NanoString, transcriptomics, and scGPT computational modeling.
• Analysis of global Irf3-/- and Irf7-/- mice.
• Deep transcriptomic profiling of lung alveolar macrophages (AMs), DC1, and DC2 subsets.

Main Results:

• Macrophages are more sensitive to TLR3 stimulation (IRF3-dependent), while DCs respond better to TLR7 activation.
• Global Irf7-/- mice showed increased survival against IAV, while Irf3-/- mice had faster recovery.
• IRF7 drives responses in AMs and DC2 cells post-IAV infection.
• scGPT simulations revealed distinct pathway regulations by IRF3 and IRF7.

Conclusions:

• IRF3 and IRF7 exhibit divergent, context-dependent roles in antiviral immunity.
• IRF3 primarily mediates rapid pathogen sensing, whereas IRF7 regulates sustained inflammation and adaptive immunity.
• Findings offer insights into targeted antiviral therapies and innate immune regulation.