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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, View ORCID ProfileCharles Y. Chiu, View ORCID ProfileKoen K. A. Van Rompay, View ORCID ProfileLark L. Coffey
doi: https://doi.org/10.1101/2020.08.11.247411
Danilo Lemos
1University of California, Davis, School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology
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Jackson B. Stuart
1University of California, Davis, School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology
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William Louie
1University of California, Davis, School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology
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Anil Singapuri
1University of California, Davis, School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology
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Ana L. Ramírez
1University of California, Davis, School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology
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Jennifer Watanabe
2University of California, Davis, California National Primate Research Center
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Jodie Usachenko
2University of California, Davis, California National Primate Research Center
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Rebekah I. Keesler
2University of California, Davis, California National Primate Research Center
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Claudia Sanchez-San Martin
3University of California, San Francisco, Department of Laboratory Medicine
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Tony Li
3University of California, San Francisco, Department of Laboratory Medicine
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Calla Martyn
3University of California, San Francisco, Department of Laboratory Medicine
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Glenn Oliveira
4The Scripps Research Institute
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Sharada Saraf
4The Scripps Research Institute
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Nathan D. Grubaugh
4The Scripps Research Institute
5Department of Epidemiology of Microbial Diseases, Yale School of Public Health
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Kristian G. Andersen
4The Scripps Research Institute
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James Thissen
6Lawrence Livermore National Laboratory
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Jonathan Allen
6Lawrence Livermore National Laboratory
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Monica Borucki
6Lawrence Livermore National Laboratory
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Konstantin A. Tsetsarkin
7Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health
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Alexander G. Pletnev
7Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health
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Charles Y. Chiu
3University of California, San Francisco, Department of Laboratory Medicine
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  • ORCID record for Charles Y. Chiu
Koen K. A. Van Rompay
2University of California, Davis, California National Primate Research Center
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Lark L. Coffey
1University of California, Davis, School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology
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  • ORCID record for Lark L. Coffey
  • For correspondence: lcoffey@ucdavis.edu
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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 intra-host mutation, M1404I, in the ZIKV polyprotein, located in NS2B. Targeted sequencing flanking position 1404 in 9 additional macaque mothers and their fetuses identified M1404I at sub-consensus frequency in the majority (5 of 9, 56%) of animals and some of their fetuses. Despite its repeated presence in pregnant macaques, M1404I occurs 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 fitness in non-pregnant 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 M1404, we observed that I1404 produced lower viremias in non-pregnant macaques and was a weaker competitor in tissues. In pregnant wildtype mice ZIKV I1404 increased the magnitude and rate of placental infection and conferred fetal infection, contrasting with M1404, which was not detected in fetuses. Although infection and dissemination rates were not different, Ae. aegypti transmitted ZIKV I1404 more poorly than 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 it in non-pregnant 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 non-pregnant 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 non-pregnant hosts.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted August 13, 2020.
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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
bioRxiv 2020.08.11.247411; doi: https://doi.org/10.1101/2020.08.11.247411
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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
bioRxiv 2020.08.11.247411; doi: https://doi.org/10.1101/2020.08.11.247411

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