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J Virol. 2018 Dec 10;93(1). pii: e01098-18. doi: 10.1128/JVI.01098-18. Print 2019 Jan 1.

Naturally Occurring Single Mutations in Ebola Virus Observably Impact Infectivity.

Wong G#1,2,3,4, He S#1, Leung A#1, Cao W#1,3, Bi Y#2,4, Zhang Z1,3, Zhu W1,3, Wang L4, Zhao Y4, Cheng K5, Liu D4, Liu W4, Kobasa D1,3, Gao GF6,4, Qiu X7,3.

Author information

1
Special Pathogens Program, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
2
Shenzhen Key Laboratory of Pathogen and Immunity, Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen Third People's Hospital, Shenzhen, China.
3
Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
4
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early Warning (CASCIRE), Chinese Academy of Sciences, Beijing, China.
5
Monoclonal Antibody Unit, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
6
Shenzhen Key Laboratory of Pathogen and Immunity, Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen Third People's Hospital, Shenzhen, China gaof@im.ac.cn xiangguo.qiu@canada.ca.
7
Special Pathogens Program, Public Health Agency of Canada, Winnipeg, Manitoba, Canada gaof@im.ac.cn xiangguo.qiu@canada.ca.
#
Contributed equally

Abstract

Sequencing of Ebola virus (EBOV) genomes during the 2014-2016 epidemic identified several naturally occurring, dominant mutations potentially impacting virulence or tropism. In this study, we characterized EBOV variants carrying one of the following substitutions: A82V in the glycoprotein (GP), R111C in the nucleoprotein (NP), or D759G in the RNA-dependent RNA polymerase (L). Compared with the wild-type (WT) EBOV C07 isolate, NP and L mutants conferred a replication advantage in monkey Vero E6, human A549, and insectivorous bat Tb1.Lu cells, while L mutants displayed a disadvantage in human Huh7 cells. The replication of the GP mutant was significantly delayed in Tb1.Lu cells and similar to that of the WT in other cells. The L mutant was less virulent, as evidenced by increased survival for mice and a significantly delayed time to death for ferrets, but increased lengths of the period of EBOV shedding may have contributed to the prolonged epidemic. Our results show that single substitutions can have observable impacts on EBOV pathogenicity and provide a framework for the study of other mutations.IMPORTANCE During the Ebola virus (EBOV) disease outbreak in West Africa in 2014-2016, it was discovered that several mutations in the virus emerged and became prevalent in the human population. This suggests that these mutations may play a role impacting viral fitness. We investigated three of these previously identified mutations (in the glycoprotein [GP], nucleoprotein [NP], or RNA-dependent RNA polymerase [L]) in cell culture, as well as in mice and ferrets, by generating recombinant viruses (based on an early West African EBOV strain) each carrying one of these mutations. The NP and L mutations appear to decrease virulence, whereas the GP mutation slightly increases virulence but mainly impacts viral tropism. Our results show that these single mutations can impact EBOV virulence in animals and have implications for the rational design of efficacious antiviral therapies against these infections.

KEYWORDS:

Ebola virus; ferrets; mice; mutations; pathogenicity

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