Assessing the risk of infection from emerging viruses or of existing viruses jumping the species barrier into novel hosts is limited by the lack of dose response data. The initial stages of the infection of a host by a virus involve a series of specific contact interactions between molecules in the host and on the virus surface. The strength of the interaction is quantified in the literature by the dissociation constant (Kd) which is determined experimentally and is specific for a given virus molecule/host molecule combination. Here, two stages of the initial infection process of host intestinal cells are modelled, namely escape of the virus in the oral challenge dose from the innate host defenses (e.g. mucin proteins in mucus) and the subsequent binding of any surviving virus to receptor molecules on the surface of the host epithelial cells. The strength of virus binding to host cells and to mucins may be quantified by the association constants, Ka and Kmucin, respectively. Here, a mechanistic dose-response model for the probability of infection of a host by a given virus dose is constructed using Ka and Kmucin which may be derived from published Kd values taking into account the number of specific molecular interactions. It is shown that the effectiveness of the mucus barrier is determined not only by the amount of mucin but also by the magnitude of Kmucin. At very high Kmucin values, slight excesses of mucin over virus are sufficient to remove all the virus according to the model. At lower Kmucin values, high numbers of virus may escape even with large excesses of mucin. The output from the mechanistic model is the probability (p1) of infection by a single virion which is the parameter used in conventional dose-response models to predict the risk of infection of the host from the ingested dose. It is shown here how differences in Ka (due to molecular differences in an emerging virus strain or new host) affect p1, and how these differences in Ka may be quantified in terms of two thermodynamic parameters, namely enthalpy and entropy. This provides the theoretical link between sequencing data and risk of infection. Lack of data on entropy is a limitation at present and may also affect our interpretation of Kd in terms of infectivity. It is concluded that thermodynamic approaches have a major contribution to make in developing dose-response models for emerging viruses.
Keywords: Asp, aspartate; CRD, carbohydrate-recognition domain; Cr, host cell receptor; Dose-response; EBOV, Zaire ebolavirus; Enthalpy; Entropy; G, Gibbs free energy; GI, gastrointestinal; GP, glycoprotein; H, enthalpy; HA, haemagglutinin; HBGA, histoblood group antigen; HeV, Hendra virus; Ka, Kmucin, association constants; Kd, dissociation constant for two molecules bound to each other; L, Avogadro number; M, molar (moles dm−3); MBP, mannose binding protein; MERS-CoV, MERS coronavirus; MRA, microbiological risk assessment; Mucin; NPC1, Niemann-Pick C1 protein; NiV, Nipah virus; NoV, norovirus; PL, phospholipid; PRR, pathogen recognition receptor; Phe, phenylalanine; R, ideal gas constant; S, entropy; SPR, surface plasmon resonance; T, temperature; TIM-1, T-cell immunoglobulin and mucin domain protein 1; VSV, vesicular stomatitis virus; Virus; k, on/off rate constant; n, number of GP/Cr molecular contacts per virus/host cell binding; pfu, plaque-forming unit; ΔGa, change in Gibbs free energy on association of virus and cell; ΔHa, change in enthalpy on association of virus and cell; ΔSa, change in entropy on association of virus and cell; ΔΔHa, change in ΔHa.
© 2018 Elsevier B.V. All rights reserved.