Stochastic model of endosomal escape of Influenza virus

TL;DR

This paper presents a stochastic model to understand how influenza virus hemagglutinin proteins undergo conformational changes during endosomal entry, highlighting the role of proton binding and the threshold of activated HAs needed for fusion.

Contribution

It introduces a novel stochastic Markov-jump process model to quantify HA activation kinetics and proton binding dynamics during influenza endosomal escape.

Findings

HA proton binding sites have high chemical barriers, stabilizing the spike at sub-acidic pH

More than 3 adjacent HAs need activation to trigger fusion

The model predicts the timing and conditions for HA conformational change

Abstract

Influenza viruses enter a cell via endocytosis after binding to the surface. During the endosomal journey, acidification triggers a conformational change of the virus spike protein hemagglutinin (HA) that results in escape of the viral genome from the endosome to the cytoplasm. A quantitative understanding of the processes involved in HA mediated fusion with the endosome is still missing. We develop here a stochastic model to estimate the change of conformation of HAs inside the endosome nanodomain. Using a Markov-jump process to model the arrival of protons to HA binding sites, we compute the kinetics of their accumulation and the mean first time for HAs to be activated. This analysis reveals that HA proton binding sites possess a high chemical barrier, ensuring a stability of the spike protein at sub-acidic pH. Finally, we predict that activating more than 3 adjacent HAs is necessary to prevent a premature fusion.