Type I Interferon Targets Alveolar Macrophages to Promote Bacterial Pneumonia after Viral Infection

Area of Science:

• Immunology
• Microbiology
• Virology

Background:

• Respiratory viral infections, including influenza A virus (IAV), respiratory syncytial virus (RSV), and human metapneumovirus (hMPV), elevate the risk of secondary Streptococcus pneumoniae (SPn) pneumonia.
• Type I interferons (IFN-I) are critical antiviral mediators, and alveolar macrophages (AMs) are key in defending the airways against bacterial pathogens.

Purpose of the Study:

• To investigate the direct impact of virus-induced Type I interferon (IFN-I) signaling on alveolar macrophage (AM) function and susceptibility to secondary Streptococcus pneumoniae (SPn) infection.
• To elucidate the role of IFN-I receptor (IFNAR1) signaling in AMs during viral infections and subsequent bacterial pneumonia.

Main Methods:

• Utilized conditional knockout mouse models lacking Ifnar1 in specific cell types.
• Employed in vivo antibody treatments to block IFN-I signaling.
• Conducted bone marrow chimeric mouse experiments and AM reconstitution assays.
• Infected mice with IAV, RSV, hMPV, and seasonal human coronavirus, followed by SPn challenge.

Main Results:

• IFN-I signaling, mediated by IFNAR1, directly impairs AM-dependent antibacterial defense.
• IFN-I intrinsically targets AMs, increasing susceptibility to SPn following IAV infection.
• RSV and hMPV infections induced significant IFN-I signaling in AMs, leading to lethal SPn susceptibility.
• Seasonal human coronavirus did not induce substantial IFN-I signaling in AMs or immune predisposition to SPn.

Conclusions:

• IFN-I inhibition of AMs is a critical mechanism driving secondary bacterial pneumonia after respiratory viral infections.
• The extent of IFN-I induction in AMs correlates with the risk of developing SPn pneumonia.
• Targeting IFN-I signaling in AMs could be a therapeutic strategy to prevent bacterial complications following viral respiratory infections.