Single-Nucleotide Polymorphisms in Human NPC1 Influence Filovirus Entry Into Cells

Area of Science:

• Virology
• Genetics
• Cell Biology

Background:

• Niemann-Pick C1 (NPC1) is a host cell receptor crucial for filovirus entry.
• Ebola virus (EBOV) glycoprotein (GP) interacts with NPC1 domain C for cell entry.
• Cell susceptibility to filoviruses is largely determined by NPC1 function.

Purpose of the Study:

• To investigate the impact of naturally occurring human NPC1 single-nucleotide polymorphisms (SNPs) on filovirus infection susceptibility.
• To determine if genetic variations in NPC1 affect cellular entry of filoviruses.

Main Methods:

• Identified 10 missense SNPs in human NPC1 using existing structural data and the NCBI SNP database.
• Generated Vero E6 cell lines stably expressing NPC1 variants with SNP substitutions.
• Assessed cell susceptibility using vesicular stomatitis virus (VSV) pseudotyped with filovirus GPs and infectious EBOV.

Main Results:

• Several NPC1 SNP substitutions led to reduced susceptibility to filovirus infection.
• Lower viral titers and smaller plaque/focus sizes were observed in cells with specific NPC1 variants.
• Demonstrated a functional impact of human NPC1 genetic variations on filovirus entry.

Conclusions:

• Naturally occurring human NPC1 SNPs can modulate host cell susceptibility to filovirus infections.
• These findings highlight the role of NPC1 genetic diversity in determining individual or population-level risk for filovirus diseases.
• NPC1 genetic variations represent potential factors influencing filovirus pathogenesis and spread.