Towards a thermodynamic mechanistic model for the effect of temperature on arthropod vector competence for transmission of arboviruses

Abstract

A B S T R A C TArboviruses such as West Nile virus (WNV), bluetongue virus (BTV), dengue virus (DENV) and chikungunya virus (CHIKV) infect their arthropod vectors over a range of average temperatures depending on the ambient temperature. How the transmission efficiency of an arbovirus (i.e. vector competence) varies with temperature influences not only the short term risk of arbovirus outbreaks in humans and livestock but also the long term impact of climate change on the geographical range of the virus. The strength of the interaction between viral surface (glyco)protein (GP) and the host cell receptor (Cr) on binding of virus to host cell is defined by the thermodynamic dissociation constant K d_receptor which is assumed to equal 10 −3 M (at 37°C) for binding of a sialic acid (SA) on the arthropod midgut epithelial cell surface to a SA-binding site on the surface of BTV, for example. Here virus binding affinity is modelled with increasing number of GP/Cr contacts at temperatures from 10°C to 35°C taking into account the change in entropy on immobilization of the whole virus on binding (ΔS a_immob ). Based on published data, three thermodynamic GP/Cr binding scenarios, namely enthalpy-driven, entropy-assisted and entropy-driven, are shown to affect the temperature sensitivity of virus binding in different ways. Thus for enthalpy-driven GP/Cr binding, viruses bind host cells much more strongly at 10°C than 35°C. A mechanistic model is developed for the number of arthropod midgut cells with bound virus and by building in a kinetic component for the rate of arbovirus replication and subsequent spread to the arthropod salivary glands, a model for the effect of temperature on vector competence is developed. The model separates the opposing effects of temperature on midgut cell binding affinity from the kinetic component of virogenesis. It successfully accommodates both increases in vector competence with temperature as for DENV and WNV in mosquitoes and decreases as for the CHIKV 2010-1909 strain in various populations of Aedes albopictus mosquitoes. Enhanced cell binding at lower temperatures through enthalpy-driven GP/Cr binding compensates for the lower replication rate to some degree such that some transmission can still occur at lower temperatures. In contrast, the strength of entropy-driven GP/Cr binding diminishes at low temperatures although there is no minimum temperature threshold for transmission efficiency. The magnitude of ΔS a_immob is an important data gap. It is concluded that thermodynamic and kinetic data obtained at the molecular level will prove important in modelling vector competence with temperature.Abbreviations: AIV, avian influenza virus; BBF, brush border fragments from midgut; C free , number of midgut epithelial cells which can bind virus with no virus bound; CHIKV, chikungunya virus; Cr, host cell receptor; C total_midgut , number of midgut epithelial cells which can bind virus; C.V T , number of arthropod midgut cells with bound arbovirus at temperature T; DENV, dengue fever virus; E A ...

How virus size and attachment parameters affect the temperature sensitivity of virus binding to host cells: Predictions of a thermodynamic model for arboviruses and HIV

“…The Cr molecule on the cell surface may be a protein as in the case of HIV (Myszka et al 2000), EBOV (Yuan et al 2015), Hendra virus (Xu et al, 2012) and MERS-CoV (Lu et al 2013) or alternatively is a sialic acid (SA) on a glycan as in the case of AIV (De Graaf and Fouchier, 2014;Fei et al 2015) and arboviruses such as bluetongue virus (BTV) (Zhang et al 2010). The thermodynamics of virus binding in terms of the changes in enthalpy (ΔH a_receptor_T ) and entropy (ΔS a_receptor_T ) on the specific interaction of the GP with the Cr receptor at temperature T during binding of virus to the host cell surface has been set out previously (Gale 2018(Gale , 2019. The interactions between the HIV GP and its CD4 cellular receptor (Myszka et al 2000;Dey et al 2007) and between the AIV haemagglutinin (HA) and its 2,3-SA or 2,6-SA receptors are enthalpy driven, i.e.…”

“…Only virus binding is considered here. Thus according to the van't Hoff Isochore, the binding affinity for a virus to its host cell at temperature T as represented by the association constant K a_virus_T would be greatly diminished for enthalpy-driven GP/Cr interactions at higher temperatures compared to lower temperatures depending on the magnitude of ΔH a_receptor_T (Gale 2019). Indeed, assuming ΔH a_receptor_T is constant over the temperature range, the more negative ΔH a_receptor_T is in magnitude, the weaker the binding at higher temperatures.…”

“…Indeed, assuming ΔH a_receptor_T is constant over the temperature range, the more negative ΔH a_receptor_T is in magnitude, the weaker the binding at higher temperatures. This presents a paradox if the K a_virus_T falls to less than ~10 14 M -1 in that higher temperatures would greatly diminish infectivity (Gale 2019).…”

“…The change in ΔH a_receptor_T with temperature is defined by the difference in heat capacities (C p ) of the GP/Cr "product" complex and the free GP/free host Cr "reactants" and is represented by ΔC p which is the slope of the lines in Figure 1 and typically ranges from ~0 kJ/mol/K to -5.0 kJ/mol/K depending on the system. The previous thermodynamic treatment of virus binding (Gale 2019) identified the entropy change (ΔS a_immob ) on immobilisation of the whole virus particle on the host cell surface as a key parameter for which there are currently no data. ΔS a_immob would be expected to be large and negative in magnitude due to the decrease in the absolute entropy on immobilisation of a large molecular entity such as a virion.…”

“…However, Frey et al (1995) reported the binding of cells expressing HIV GP on their surface to CD4 + T cells over the temperature range of 0°C to 42°C. It is known that increasing host membrane fluidity at higher temperature allows effective recruitment of more Cr molecules to bind the HIV virion (Harada et al 2004) such that the number, n, of GP/Cr contacts increases with temperature (Frey et al 1995), and that increasing n can overcome both the effect of temperature on decreasing the GP/Cr binding affinity and the effect of a large negative ΔS a_immob (Gale 2019). The thermodynamic HIV binding model here is therefore modified to accommodate increasing n with temperature and so attempt to reproduce the results of Frey et al, (1995).…”