Routes of Zika virus dissemination in the testis and epididymis of immunodeficient mice

Konstantin A. Tsetsarkin, Olga A. Maximova, Guangping Liu, Heather Kenney, Natalia Teterina, Marshall E. Bloom, Jeffrey M. Grabowski, Luwanika Mlera, Bianca M. Nagata, Ian Moore, Craig Martens, Emerito Amaro-Carambot, Elaine W. Lamirande, Stephen S. Whitehead and Alexander G. Pletnev ()
Additional contact information
Konstantin A. Tsetsarkin: National Institutes of Health (NIH)
Olga A. Maximova: National Institutes of Health (NIH)
Guangping Liu: National Institutes of Health (NIH)
Heather Kenney: National Institutes of Health (NIH)
Natalia Teterina: National Institutes of Health (NIH)
Marshall E. Bloom: Laboratory of Virology, Rocky Mountain Laboratories, NIAID, NIH
Jeffrey M. Grabowski: Laboratory of Virology, Rocky Mountain Laboratories, NIAID, NIH
Luwanika Mlera: Laboratory of Virology, Rocky Mountain Laboratories, NIAID, NIH
Bianca M. Nagata: Comparative Medicine Branch, NIAID, NIH
Ian Moore: Comparative Medicine Branch, NIAID, NIH
Craig Martens: RT Branch, Rocky Mountain Laboratories, NIAID, NIH
Emerito Amaro-Carambot: Laboratory of Viral Diseases, NIAID, NIH
Elaine W. Lamirande: Laboratory of Viral Diseases, NIAID, NIH
Stephen S. Whitehead: Laboratory of Viral Diseases, NIAID, NIH
Alexander G. Pletnev: National Institutes of Health (NIH)

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Sexual transmission and persistence of Zika virus (ZIKV) in the male reproductive tract (MRT) poses new challenges for controlling virus outbreaks and developing live-attenuated vaccines. To elucidate routes of ZIKV dissemination in the MRT, we here generate microRNA-targeted ZIKV clones that lose the infectivity for (1) the cells inside seminiferous tubules of the testis, or (2) epithelial cells of the epididymis. We trace ZIKV dissemination in the MRT using an established mouse model of ZIKV pathogenesis. Our results support a model in which ZIKV infects the testis via a hematogenous route, while infection of the epididymis can occur via two routes: (1) hematogenous/lymphogenous and (2) excurrent testicular. Co-targeting of the ZIKV genome with brain-, testis-, and epididymis-specific microRNAs restricts virus infection of these organs, but does not affect virus-induced protective immunity in mice and monkeys. These defined alterations of ZIKV tropism represent a rational design of a safe live-attenuated ZIKV vaccine.

Date: 2018
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DOI: 10.1038/s41467-018-07782-x

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