Cell-intrinsic regulation of phagocyte function by interferon lambda during pulmonary viral, bacterial...

Area of Science:

• Immunology
• Infectious Diseases
• Respiratory Medicine

Background:

• Influenza infections often lead to severe illness, frequently complicated by secondary bacterial infections like methicillin-resistant Staphylococcus aureus (MRSA).
• Influenza alters immune responses, increasing susceptibility to these super-infections and causing significant immunopathology.
• Type III interferons (IFNλ) are explored for antiviral therapies due to their ability to limit viral replication with reduced inflammation, but their role in immune cell function during super-infections is unclear.

Purpose of the Study:

• To investigate the impact of Type III interferons (IFNλ) on immune cell function during secondary bacterial super-infections following influenza.
• To determine the specific immune cell types and signaling pathways involved in IFNλ-mediated regulation of bacterial clearance.

Main Methods:

• Wild-type and IFNLR1-/- mice were infected with influenza A followed by Staphylococcus aureus (MRSA).
• Mixed bone marrow chimeras were used to assess cell-intrinsic effects of IFNLR1 signaling.
• Depletion of IFNLR1 specifically on CX3CR1 expressing myeloid cells and neutrophils was performed to evaluate their roles.

Main Results:

• Mice lacking global IFNLR1 exhibited enhanced bacterial clearance, attributed to increased phagocyte uptake.
• This enhanced clearance was cell-intrinsic to myeloid cells.
• Depleting IFNLR1 on CX3CR1+ myeloid cells, but not neutrophils, significantly reduced bacterial burden.

Conclusions:

• IFNλ signaling in the lung impedes bacterial clearance during influenza-associated super-infections.
• IFNλ signaling has a direct, cell-intrinsic role in regulating the function of myeloid immune cells during bacterial super-infections.