Overcoming host range barriers through single mutations

Evolutionary genetics and vector adaptation of recombinant viruses of the western equine encephalitis antigenic complex provides new insights into alphavirus diversity and host switching

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Alphaviruses are a group of arthropod-borne positive-sense RNA viruses that contain many important human and veterinary pathogens. A notable example is Chikungunya virus (CHIKV), which although historically was regarded as an anecdotal human pathogen of little concern (and hence was little-studied), has re-emerged in the last decade to cause unprecedented large-scale outbreaks of disease involving cumulatively millions of people on a near global scale. So what are the factors driving this re-emergence? One of the primary reasons for the enhanced geographical spread of the virus was its recent adaptation to a new vector species, Aedes albopictus (commonly known as the Asian tiger mosquito), through mutations in its envelope proteins. Thus, investigating how alphaviruses can jump species to infect and be efficiently transmitted by previously less or non-susceptible hosts is critical to understanding the factors that influence alphavirus emergence or re-emergence. 

The impetus for this work was the recognition that a recombinant alphavirus, Fort Morgan virus (FMV), did not infect Aedes albopictus cell cultures. This is in stark contrast to the other alphaviruses derived from the same recombination event, Highlands J virus (HJV) and western equine encephalitis virus (WEEV), and suggested that adaptation of FMV to an aberrant (non-mosquito) host in nature, the swallow bug, resulted in the virus not being able to infect mosquitoes. Our objectives were to determine if FMV could adapt to replicate in mosquito cell cultures, and if so, what were the genetic mechanisms that were involved in this host range expansion. Our original hunch was that, similar to CHIKV adapting to Aedes albopictus, the control(s) for mosquito infection were likely going to be in the E1 or E2 surface glycoproteins. To our surprise, the one conserved mutation that we observed in all of the mosquito-adapted viruses was not in the surface proteins of the virus, but rather in the nsP4 polymerase. Our second surprise came when we found a very similar basic mutation (Q to K rather than Q to R) at the same analogous site in nsP4 previously reported in another alphavirus, Sindbis virus (SINV), which effected minus-strand synthesis. This finding suggested that the nsP4 mutation in FMV might also effect replication of the virus in a host-specific manner and thus potentially be critical to allow mosquito cell infection. In a broader sense, these findings demonstrate that host range barriers can be overcome with single mutations and suggests that such plasticity has likely facilitated the emergence of alphaviruses as cosmopolitan pathogens of increasing medical and veterinary importance. 

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Figure: (A) Multi-step single growth curve analysis of Fort Morgan virus (FMV) in Aedes albopictus (C6/36) cells at 28 °C. Two viruses are shown: (i) the prototype strain of FMV (CM4-146) and (ii) a C6/36-adapted strain of CM4-146 (C6-1). Note that while CM4-146 does not replicate in Aedes albopictus cultures, the C6-1 strain (containing the nsP4 192R mutation) reaches a maximum titer of 106.47 PFU/mL by day 6 post-infection. (B) A female Aedes albopictus beginning a blood meal. Photo courtesy of James Gathany, Centers for Disease Control and Prevention.

Introducing the Author

Andrew Allison photo
Dr. Andrew Allison is a post-doctoral fellow in the Baker Institute for Animal Health, Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University in Ithaca, New York, USA 

About the Research
Evolutionary genetics and vector adaptation of recombinant viruses of the western equine encephalitis antigenic complex provides new insights into alphavirus diversity and host switching

Virology, Volume 474, January 2015, Pages 154–162
Andrew B. Allison, David E. Stallknecht, Edward C. Holmes

 Read the full article on ScienceDirect

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