Ancestral allele of DNA polymerase gamma modifies antiviral tolerance

Area of Science:

• Mitochondrial biology
• Immunology
• Neuroscience

Background:

• Mitochondria regulate antiviral responses via released mitochondrial DNA (mtDNA) and RNA (mtRNA) fragments.
• Mitochondrial diseases, particularly Mitochondrial Recessive Ataxia Syndrome (MIRAS), have understudied links to antiviral mechanisms.
• The POLG1 gene, crucial for mtDNA replication, is implicated in MIRAS.

Purpose of the Study:

• Investigate the role of POLG1 and its p.W748S variant in antiviral defense.
• Determine how POLG1 defects influence disease manifestation in MIRAS patients.
• Explore the impact of POLG1 mutations on innate immune responses and disease phenotypes.

Main Methods:

• Analysis of patient data and knock-in mouse models of MIRAS.
• Assessment of mtDNA and mtRNA release upon viral infection (HSV-1, TBEV, SARS-CoV-2).
• Evaluation of innate immune responses, including type-I interferon (IFN-I) signaling.
• Population data analysis of Finnish individuals carrying the POLG1 p.W748S mutation.

Main Results:

• The POLG1 p.W748S variant impairs antiviral defense against DNA and RNA viruses.
• This variant compromises mtDNA replisome stability, leading to mtDNA depletion, exacerbated by infection.
• Reduced mtDNA/mtRNA release and a delayed IFN response in MIRAS patients confer a viral replicative advantage.
• POLG1 p.W748S carriers exhibit enriched immunodeficient traits, epilepsy, and liver disease.

Conclusions:

• POLG1 defects, specifically the p.W748S variant, compromise antiviral tolerance.
• These defects lead to increased susceptibility to viral infections and trigger neurological and hepatic pathologies.
• Findings expand the understanding of the mitochondrial disease spectrum, including epilepsy, ataxia, and parkinsonism.