The challenge of using experimental infectivity data in risk assessment for Ebola virus: why ecology may be important

Abstract

SummaryAnalysis of published data shows that experimental passaging of Zaire ebolavirus (EBOV) in guinea pigs changes the risk of infection per plaqueforming unit (PFU), increasing infectivity to some species while decreasing infectivity to others. Thus, a PFU of monkey-adapted EBOV is 10 7 -fold more lethal to mice than a PFU adapted to guinea pigs. The first conclusion is that the infectivity of EBOV to humans may depend on the identity of the donor species itself and, on the basis of limited epidemiological data, the question is raised as to whether bat-adapted EBOV is less infectious to humans than nonhuman primate (NHP)-adapted EBOV. Wildlife species such as bats, duikers and NHPs are naturally infected by EBOV through different species giving rise to EBOV with different wildlife species-passage histories (heritages). Based on the ecology of these wildlife species, three broad 'types' of EBOVinfected bushmeat are postulated reflecting differences in the number of passages within a given species, and hence the degree of adaptation of the EBOV present. The second conclusion is that the prior species-transmission chain may affect the infectivity to humans per PFU for EBOV from individuals of the same species. This is supported by the finding that the related Marburg marburgvirus requires ten passages in mice to fully adapt. It is even possible that the evolutionary trajectory of EBOV could vary in individuals of the same species giving rise to variants which are more or less virulent to humans and that the probability of a given trajectory is related to the heritage. Overall the ecology of the donor species (e.g. dog or bushmeat species) at the level of the individual animal itself may determine the risk of infection per PFU to humans reflecting the heritage of the virus and may contribute to the sporadic nature of EBOV outbreaks.

Could Bat Cell Temperature and Filovirus Filament Length Explain the Emergence of Ebola Virus in Mammals? Predictions of a Thermodynamic Model

“…It is proposed here that these failures to demonstrate experimental infection in arthropods with low challenge doses in small numbers of arthropods do not provide definitive proof that arthropods are refractory to filovirus infection or that filoviruses do not originate from an arthropod source. Indeed, by analogy to trends in the numbers of LD 50 /pfu with passaging of EBOV in mammals (Gale et al., ), it is suggested that much higher doses of virus than the 300–1200 pfu per individual arthropod used by Swanepoel et al. () and Turell et al.…”

“…via an insectivorous bat) from an insect reservoir. Indeed, it is well known that the lethal dose 50% (LD 50 )/pfu ratio for EBOV varies hugely with passaging in mammalian species (guinea pigs) (see Gale et al., ). For example, analysing data from Ryabchikova et al.…”

“…() showed that the number of mice LD 50 /pfu drops from 287 mice LD 50 /pfu for green monkey ( Cercopithecus aethiops ) adapted EBOV down to <9.0 × 10 −6 mice LD 50 /pfu after four passages in guinea pigs ( Cavia porcellus ). Thus, a pfu of Ebola virus C. porcellus ‐wt is >10 7 ‐fold less infectious to mice than a pfu of Ebola virus C. aethiops ‐wt (Gale et al., ). So if the EBOV‐tc used by Swanepoel et al.…”

Using thermodynamic parameters to calibrate a mechanistic dose-response for infection of a host by a virus

“…An additional complication is that the pathogen may adapt to the new host, such that its infectivity increases. This is well established for filoviruses in laboratory animals where the infectivity per plaque-forming unit (pfu) may change by several orders of magnitude with passaging (Gale et al, 2016), and has recently been demonstrated for EBOV Makona adapting to humans through an amino acid substitution in its glycoprotein during the recent catastrophic outbreak in West Africa (Diehl et al, 2016;Urbanowicz et al, 2016). That outbreak also raised many questions regarding the unknown potential for companion animals (cats and dogs) to serve either as a reservoir or vector for the virus and so be involved in transmission of EBOV to humans and other animals.…”

“…Indeed, it has been proposed that the infectivity to humans of an EBOV pfu may differ not only from bushmeat samples from different wildlife species (e.g. fruits bats and nonhuman primates) but also from different individuals of the same species depending on the degree of host adaptation (Gale et al, 2016). In effect no two pieces of bushmeat from EBOVinfected wildlife may be the same in terms of infectivity to humans, although this remains to be proved.…”