Stochastic Model of Acidification, Activation of Hemagglutinin and Escape of Influenza Viruses from an Endosome

Abstract

Influenza viruses enter the cell inside an endosome. 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 into the cytoplasm. It is still unclear how the interplay between acidification and HA conformation changes affects the kinetics of the viral endosomal escape. We develop here a stochastic model to estimate the change of conformation of HAs inside the endosome nanodomain. Using a Markov process, we model the arrival of protons to HA binding sites and compute the kinetics of their accumulation. We compute the Mean First Passage Time (MFPT) of the number of HA bound sites to a threshold, which is used to estimate the HA activation rate for a given pH (i.e. proton concentration). The present analysis reveals that HA proton binding sites possess a high chemical barrier, ensuring a stability of the spike protein at sub-acidic pH. We predict that activating more than 3 adjacent HAs is necessary to trigger endosomal fusion and this configuration prevents premature release of viruses from early endosomes.

Microtubules in Influenza Virus Entry and Egress

“…Specifically, protons weaken the interactions between HA-M1, M1-M1, and M1-vRNP, while the K + ions promote the solubilisation of vRNP complexes. Within LEs, where the microenvironmental pH reaches less than 5.5, irreversible changes take place within the viral core, which are needed for the efficient dissociation of the viral shell from vRNP complexes [81,92].…”

Fusion and fission events regulate endosome maturation and viral escape

“…Also, the authors of Ref. [14] consider the acidification of individual endosomes, without considering interactions between them. Finally, it is worth mentioning that, in Ref.…”

“…Our approach here takes a different route beyond deterministic descriptions of endosomal dynamics at the cellular level [19,26,28,29], or at the single endosome level [14,15,23]. As we have discussed earlier, the former presumes that Rab dynamics at the cellular scale can be studied from the observation of endosomal averages, and, the latter, focuses on biochemical reactions on the endosome membrane, which do not include the interaction between endosomes.…”

“…Besides their role as experimental markers, different Rab molecules have been identified as central regulators of the endosomal transport pathway [13]. Of particular relevance, is the fact that endosomal pH has been experimentally linked to different levels of Rab5 and Rab7 [5,[13][14][15]. Given the large variability observed in viral escape times [9,11,16], it is timely to ask ourselves the following questions: (i) is pH alone the main trigger of viral escape, (ii) is the pH dependence gradual (analogical) or abrupt (digital), and (iii) can endosome maturation and dynamics explain the observed heterogeneity in the distribution of viral escape times.…”

Statistical modeling of cell‐to‐cell variability in viral infection during passaging in suspension cell culture: Application in Monte‐Carlo simulation

“…Moreover, a computational framework is proposed that focuses on kinetic model selection for HIV viral entry through binding to receptor and coreceptor expression based on their predictions to infectivity measurement (Mistry, D'Orsogna, Webb, Lee, & Chou, 2016). Similarly, in other biological systems, the Monte‐Carlo simulations have been performed to study endosomal fusion and escape of influenza (Lagache, Sieben, Meyer, Herrmann, & Holcman, 2017) and gene expression profiles in normal and cancer cells (Ogundijo & Wang, 2017; Zhang et al, 1997). The probability distribution for protein expression and the number of packaged virus in this study corresponds biologically to the variability in the expression and packaging process, with some cells getting infected and undergoing viral protein expression without mutations, while other cells in the suspension culture undergo mutations due to the transposon insertion (Giri et al, 2010).…”