Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection

Area of Science:

• Immunology
• Virology
• Metabolic Research

Background:

• Type I Interferons (IFN-I) are critical for antiviral defense, primarily produced by plasmacytoid dendritic cells (pDCs).
• pDCs exhibit a transient IFN-I production capacity, leading to susceptibility to secondary infections, with underlying mechanisms poorly understood.
• Viral infections impact host immune cell function, including metabolic pathways essential for immune responses.

Purpose of the Study:

• To elucidate the mechanisms behind the loss of IFN-I production capacity in pDCs during viral infections.
• To identify key regulators of pDC metabolism and function in the context of viral infections.
• To explore the role of specific metabolic enzymes in maintaining pDC antiviral activity and preventing immune exhaustion.

Main Methods:

• Analysis of pDC metabolic capacity (oxidative and glycolytic) following viral infection.
• Investigation of lactate dehydrogenase B (LDHB) expression and its correlation with IFN-I production in pDCs from mice and humans.
• In vitro and in vivo experiments to assess the impact of LDHB preservation or deficiency on pDC function, viral control, and infection-associated pathology.

Main Results:

• Viral infection significantly reduces the oxidative and glycolytic metabolic capacity of pDCs.
• LDHB is identified as a positive regulator of pDC IFN-I production; LDHB deficiency impairs pDC metabolism, IFN-I production, and viral control.
• Preserving LDHB expression partially restores the function of exhausted pDCs, while its restoration in vivo exacerbates IFNAR-dependent pathology.

Conclusions:

• LDHB plays a crucial role in maintaining pDC metabolic function and IFN-I production during viral infections.
• The study identifies a mechanism for balancing antiviral immunity and pathology by regulating pDC function via LDHB.
• Findings provide insight into the infection-driven inhibition of pDCs and suggest LDHB as a potential therapeutic target.