Evaluating the impact of NPC1 single nucleotide polymorphisms on entry efficiency of filoviruses in vitro:...

Ebola and Marburg viruses are highly pathogenic filoviruses that cause severe hemorrhagic fever in humans, with case fatality rates reaching approximately 50 %. These viruses pose significant public health challenges owing to their potential for large-scale outbreaks. A key step in their infection process is the interaction between the Niemann-Pick C1 (NPC1) protein on host cells and the viral glycoprotein (GP), which is responsible for viral entry into cells. Genetic variations in NPC1 caused by single nucleotide polymorphisms (SNPs) can lead to amino acid substitutions, potentially altering the efficiency of viral entry. To better understand this process, we developed an agent-based model (ABM) to simulate viral plaque growth with spatial resolution beyond traditional models. By applying this model, we quantified how naturally occurring SNPs at GP-binding interface of NPC1, such as D508N, P424A, and S425L, reduced entry efficiency of both Ebola and Marburg viruses. Notably, the P424A substitution led to a 53 % reduction in Ebola virus entry efficiency compared to the wild-type. Our findings highlight the potential of computational modeling to uncover the impact of genetic variations on viral infections and provide insights that may inform therapeutic strategies against these deadly viruses.