Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis

Area of Science:

• Infectious Diseases
• Immunology
• Neuroscience

Background:

• Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome (HFRS), rarely leading to encephalitis.
• The pathogenesis of hantavirus-induced encephalitis remains largely unknown.

Purpose of the Study:

• To investigate if genetic defects in innate anti-viral immunity, specifically Toll-like receptor 3 (TLR3) mutations, contribute to PUUV encephalitis.
• To explore the functional impact of identified TLR3 variants on immune response.

Main Methods:

• Exome sequencing was performed on seven adult patients with acute PUUV infection and encephalitis.
• Functional assays using TLR3-deficient cell lines and patient-derived fibroblasts were conducted to assess cytokine induction.
• Mutant and wild-type TLR3 expression was analyzed in response to poly(I:C) stimulation.

Main Results:

• A novel heterozygous TLR3 p.L742F variant was identified in 29% of the studied PUUV encephalitis patients.
• The TLR3 p.L742F variant showed reduced poly(I:C)-stimulated cytokine (IFN-λ, IL-6) induction in functional assays.
• Impaired cytokine production was observed in fibroblasts from patients carrying the TLR3 L742F/WT genotype.

Conclusions:

• Heterozygous TLR3 mutations may be a predisposing factor for Puumala hantavirus encephalitis.
• This finding suggests a potential genetic link between TLR3 immune defects and severe hantavirus neurological disease.
• Further research is warranted to explore TLR3's role in encephalitis caused by PUUV and other hantaviruses.