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Genetic Diversity and Evolution | Spotlight

Two Sides of a Coin: a Zika Virus Mutation Selected in Pregnant Rhesus Macaques Promotes Fetal Infection in Mice but at a Cost of Reduced Fitness in Nonpregnant Macaques and Diminished Transmissibility by Vectors

Danilo Lemos, Jackson B. Stuart, William Louie, Anil Singapuri, Ana L. Ramírez, Jennifer Watanabe, Jodie Usachenko, Rebekah I. Keesler, Claudia Sanchez-San Martin, Tony Li, Calla Martyn, Glenn Oliveira, Sharada Saraf, Nathan D. Grubaugh, Kristian G. Andersen, James Thissen, Jonathan Allen, Monica Borucki, Konstantin A. Tsetsarkin, Alexander G. Pletnev, Charles Y. Chiu, Koen K. A. Van Rompay, Lark L. Coffey
Colin R. Parrish, Editor
Danilo Lemos
aUniversity of California, Davis, School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology, Davis, California, USA
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Jackson B. Stuart
aUniversity of California, Davis, School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology, Davis, California, USA
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William Louie
aUniversity of California, Davis, School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology, Davis, California, USA
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Anil Singapuri
aUniversity of California, Davis, School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology, Davis, California, USA
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Ana L. Ramírez
aUniversity of California, Davis, School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology, Davis, California, USA
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Jennifer Watanabe
bUniversity of California, Davis, California National Primate Research Center, Davis, California, USA
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Jodie Usachenko
bUniversity of California, Davis, California National Primate Research Center, Davis, California, USA
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Rebekah I. Keesler
bUniversity of California, Davis, California National Primate Research Center, Davis, California, USA
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Claudia Sanchez-San Martin
cUniversity of California, San Francisco, Department of Laboratory Medicine, San Francisco, California, USA
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Tony Li
cUniversity of California, San Francisco, Department of Laboratory Medicine, San Francisco, California, USA
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Calla Martyn
cUniversity of California, San Francisco, Department of Laboratory Medicine, San Francisco, California, USA
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Glenn Oliveira
dThe Scripps Research Institute, San Diego, California, USA
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Sharada Saraf
dThe Scripps Research Institute, San Diego, California, USA
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Nathan D. Grubaugh
dThe Scripps Research Institute, San Diego, California, USA
eDepartment of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, USA
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Kristian G. Andersen
dThe Scripps Research Institute, San Diego, California, USA
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James Thissen
fLawrence Livermore National Laboratory, Livermore, California, USA
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Jonathan Allen
fLawrence Livermore National Laboratory, Livermore, California, USA
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Monica Borucki
fLawrence Livermore National Laboratory, Livermore, California, USA
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Konstantin A. Tsetsarkin
gLaboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Alexander G. Pletnev
gLaboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Charles Y. Chiu
cUniversity of California, San Francisco, Department of Laboratory Medicine, San Francisco, California, USA
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Koen K. A. Van Rompay
bUniversity of California, Davis, California National Primate Research Center, Davis, California, USA
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Lark L. Coffey
aUniversity of California, Davis, School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology, Davis, California, USA
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Colin R. Parrish
Cornell University
Roles: Editor
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DOI: 10.1128/JVI.01605-20
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ABSTRACT

Although fetal death is now understood to be a severe outcome of congenital Zika syndrome, the role of viral genetics is still unclear. We sequenced Zika virus (ZIKV) from a rhesus macaque fetus that died after inoculation and identified a single intrahost substitution, M1404I, in the ZIKV polyprotein, located in nonstructural protein 2B (NS2B). Targeted sequencing flanking position 1404 in 9 additional macaque mothers and their fetuses identified M1404I at a subconsensus frequency in the majority (5 of 9, 56%) of animals and some of their fetuses. Despite its repeated presence in pregnant macaques, M1404I has occurred rarely in humans since 2015. Since the primary ZIKV transmission cycle is human-mosquito-human, mutations in one host must be retained in the alternate host to be perpetuated. We hypothesized that ZIKV I1404 increases viral fitness in nonpregnant macaques and pregnant mice but is less efficiently transmitted by vectors, explaining its low frequency in humans during outbreaks. By examining competitive fitness relative to that of ZIKV M1404, we observed that ZIKV I1404 produced lower viremias in nonpregnant macaques and was a weaker competitor in tissues. In pregnant wild-type mice, ZIKV I1404 increased the magnitude and rate of placental infection and conferred fetal infection, in contrast to ZIKV M1404, which was not detected in fetuses. Although infection and dissemination rates were not different, Aedes aegypti mosquitoes transmitted ZIKV I1404 more poorly than ZIKV M1404. Our data highlight the complexity of arbovirus mutation-fitness dynamics and suggest that intrahost ZIKV mutations capable of augmenting fitness in pregnant vertebrates may not necessarily spread efficiently via mosquitoes during epidemics.

IMPORTANCE Although Zika virus infection of pregnant women can result in congenital Zika syndrome, the factors that cause the syndrome in some but not all infected mothers are still unclear. We identified a mutation that was present in some ZIKV genomes in experimentally inoculated pregnant rhesus macaques and their fetuses. Although we did not find an association between the presence of the mutation and fetal death, we performed additional studies with ZIKV with the mutation in nonpregnant macaques, pregnant mice, and mosquitoes. We observed that the mutation increased the ability of the virus to infect mouse fetuses but decreased its capacity to produce high levels of virus in the blood of nonpregnant macaques and to be transmitted by mosquitoes. This study shows that mutations in mosquito-borne viruses like ZIKV that increase fitness in pregnant vertebrates may not spread in outbreaks when they compromise transmission via mosquitoes and fitness in nonpregnant hosts.

FOOTNOTES

    • Received 8 August 2020.
    • Accepted 24 September 2020.
    • Accepted manuscript posted online 30 September 2020.
  • Supplemental material is available online only.

  • Copyright © 2020 Lemos et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Two Sides of a Coin: a Zika Virus Mutation Selected in Pregnant Rhesus Macaques Promotes Fetal Infection in Mice but at a Cost of Reduced Fitness in Nonpregnant Macaques and Diminished Transmissibility by Vectors
Danilo Lemos, Jackson B. Stuart, William Louie, Anil Singapuri, Ana L. Ramírez, Jennifer Watanabe, Jodie Usachenko, Rebekah I. Keesler, Claudia Sanchez-San Martin, Tony Li, Calla Martyn, Glenn Oliveira, Sharada Saraf, Nathan D. Grubaugh, Kristian G. Andersen, James Thissen, Jonathan Allen, Monica Borucki, Konstantin A. Tsetsarkin, Alexander G. Pletnev, Charles Y. Chiu, Koen K. A. Van Rompay, Lark L. Coffey
Journal of Virology Nov 2020, 94 (24) e01605-20; DOI: 10.1128/JVI.01605-20

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Two Sides of a Coin: a Zika Virus Mutation Selected in Pregnant Rhesus Macaques Promotes Fetal Infection in Mice but at a Cost of Reduced Fitness in Nonpregnant Macaques and Diminished Transmissibility by Vectors
Danilo Lemos, Jackson B. Stuart, William Louie, Anil Singapuri, Ana L. Ramírez, Jennifer Watanabe, Jodie Usachenko, Rebekah I. Keesler, Claudia Sanchez-San Martin, Tony Li, Calla Martyn, Glenn Oliveira, Sharada Saraf, Nathan D. Grubaugh, Kristian G. Andersen, James Thissen, Jonathan Allen, Monica Borucki, Konstantin A. Tsetsarkin, Alexander G. Pletnev, Charles Y. Chiu, Koen K. A. Van Rompay, Lark L. Coffey
Journal of Virology Nov 2020, 94 (24) e01605-20; DOI: 10.1128/JVI.01605-20
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KEYWORDS

Zika virus
arbovirus
congenital Zika syndrome
emergence
experimental infection
fitness
Flavivirus
mouse
mutation
nonhuman primate

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