A TLR8 Variant Identified From Whole Exome Sequencing as a Sepsis-Prone Mutation

Area of Science:

• Genomics
• Immunology
• Critical Care Medicine

Background:

• Sepsis is a major global health threat, with host immune responses significantly impacting patient outcomes.
• Host genetic variations are increasingly recognized as key determinants of sepsis susceptibility and severity.
• Whole exome sequencing (WES) is a powerful tool for identifying disease-causing mutations, particularly in critical illnesses.

Purpose of the Study:

• To investigate the role of host genomic variants in sepsis susceptibility and severity using WES.
• To identify specific genetic variants, such as those in Toll-like receptor 8 (TLR8), that influence sepsis outcomes.
• To explore the functional consequences of identified variants on immune cell responses.

Main Methods:

• Whole exome sequencing (WES) was performed on 31 sepsis patients across pediatric and adult age groups.
• Single-cell RNA sequencing analyzed peripheral blood mononuclear cells to assess gene expression, particularly for TLR8.
• Functional studies evaluated the impact of a specific TLR8 variant on cytokine secretion (e.g., IFN-β) following ligand stimulation.

Main Results:

• Multiple high- and medium-impact genetic variants were identified in sepsis patients.
• A high-impact TLR8 variant (rs3764880: A>G; p.Met1Val) was found across all age groups, predominantly in bacterial sepsis cases.
• The TLR8 variant was associated with elevated TLR8 expression in non-classical monocytes and enhanced interferon-beta (IFN-β) secretion upon stimulation, suggesting dysregulated TLR8 signaling.

Conclusions:

• The identified TLR8 variant may contribute to sepsis pathophysiology by amplifying IFN-β-mediated monocyte responses, potentially exacerbating sepsis severity.
• This study highlights the importance of integrating genomic and immunologic analyses to understand host determinants of sepsis.
• TLR8 emerges as a potential biomarker and therapeutic target for precision medicine approaches in bacterial sepsis.