Rapid evolution of enhanced zika virus virulence during direct vertebrate transmission chains

Kasen K. Riemersma, Anna S. Jaeger, Chelsea M. Crooks, Katarina M. Braun, James Weger-Lucarelli, Gregory D. Ebel, Thomas C. Friedrich, Matthew T. Aliota

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Zika virus (ZIKV) has the unusual capacity to circumvent natural alternating mosquito-human transmission and be directly transmitted human-to-human via sexual and vertical routes. The impact of direct transmission on ZIKV evolution and adaptation to vertebrate hosts is unknown. Here we show that molecularly barcoded ZIKV rapidly adapted to a mammalian host during direct transmission chains in mice, coincident with the emergence of an amino acid substitution previously shown to enhance virulence. In contrast, little to no adaptation of ZIKV to mice was observed following chains of direct transmission in mosquitoes or alternating host transmission. Detailed genetic analyses revealed that ZIKV evolution in mice was generally more convergent and subjected to more relaxed purifying selection than in mosquitoes or alternate passages. These findings suggest that prevention of direct human transmission chains may be paramount to resist gains in ZIKV virulence. Importance We used experimental evolution to model chains of direct and indirect Zika virus (ZIKV) transmission by serially passaging a synthetic swarm of molecularly barcoded ZIKV within and between mosquitoes and mice. We observed that direct mouse transmission chains facilitated a rapid increase in ZIKV replication and enhanced virulence in mice. These findings demonstrate that ZIKV is capable of rapid adaptation to a vertebrate host and indicate that direct human-to-human transmission could pose a greater threat to public health than currently realized.

Original languageEnglish (US)
Article numbere02218
JournalJournal of virology
Issue number8
Early online dateFeb 3 2021
StatePublished - Apr 2021

Bibliographical note

Funding Information:
Funding for this project came from DHHS/PHS/NIH R21AI131454. The publication's contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or NIH.

Funding Information:
Genetic drift and strong purifying selection appeared to be the predominant evolutionary forces during serial mosquito and alternating passage. This is supported by the

Publisher Copyright:
Copyright © 2021 American Society for Microbiology. All Rights Reserved.


  • Aedes aegypti
  • Experimental evolution
  • Flavivirus
  • Host cycling
  • Pathogenesis
  • Virulence
  • Zika virus

PubMed: MeSH publication types

  • Journal Article


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