Research Article: Comparison of intra- and inter-host genetic diversity in rabies virus during experimental cross-species transmission

Date Published: June 20, 2019

Publisher: Public Library of Science

Author(s): Emilie M. Bonnaud, Cécile Troupin, Laurent Dacheux, Edward C. Holmes, Elodie Monchatre-Leroy, Marion Tanguy, Christiane Bouchier, Florence Cliquet, Jacques Barrat, Hervé Bourhy, Adam S. Lauring.


The development of high-throughput genome sequencing enables accurate measurements of levels of sub-consensus intra-host virus genetic diversity and analysis of the role played by natural selection during cross-species transmission. We analysed the natural and experimental evolution of rabies virus (RABV), an important example of a virus that is able to make multiple host jumps. In particular, we (i) analyzed RABV evolution during experimental host switching with the goal of identifying possible genetic markers of host adaptation, (ii) compared the mutational changes observed during passage with those observed in natura, and (iii) determined whether the colonization of new hosts or tissues requires adaptive evolution in the virus. To address these aims, animal infection models (dog and fox) and primary cell culture models (embryo brain cells of dog and fox) were developed and viral variation was studied in detail through deep genome sequencing. Our analysis revealed a strong unidirectional host evolutionary effect, as dog-adapted rabies virus was able to replicate in fox and fox cells relatively easily, while dogs or neuronal dog cells were not easily susceptible to fox adapted-RABV. This suggests that dog RABV may be able to adapt to some hosts more easily than other host variants, or that when RABV switched from dogs to red foxes it lost its ability to adapt easily to other species. Although no difference in patterns of mutation variation between different host organs was observed, mutations were common following both in vitro and in vivo passage. However, only a small number of these mutations also appeared in natura, suggesting that adaptation during successful cross-species virus transmission is a complex, multifactorial evolutionary process.

Partial Text

RNA viruses are characterized by high rates of evolutionary change, the result of replication with error-prone RNA-dependent RNA polymerases and a combination of natural selection and sometimes recombination, enabling rapid adaptation to changing environments, including new host species and cell types [1, 2]. Understanding the evolutionary mechanisms that shape virus genetic diversity is therefore central to determining cross-species transmission and potentially disease emergence.

Cross-species virus transmission leading to disease emergence is a major public health concern.




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