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Zika Virus Infects Human Sertoli Cells And Trespasses The Blood-Testes Barrier To Gain Entry Into The Seminiferous Epithelium
|Title:||Zika Virus Infects Human Sertoli Cells And Trespasses The Blood-Testes Barrier To Gain Entry Into The Seminiferous Epithelium|
|Contributors:||Biomedical Sciences (Tropical Medicine) (department)|
|Date Issued:||Aug 2017|
|Publisher:||University of Hawaiʻi at Mānoa|
|Abstract:||Over the past decade, Zika virus (ZIKV) has re-emerged as a pathogen of major health|
concern in the Western Hemisphere. Specifically, since 2007, 76 countries have announced
new outbreaks of ZIKV, 29 of which also report increased incidence of CNS malformations
such as microcephaly and also Guillain-Barre Syndrome . These alarming statistics
combined with the unique ability of ZIKV to be transmitted both sexually and in utero highlight
the urgent need to study the mechanisms of ZIKV pathogenesis in order to ultimately develop
vaccines, effective anti-viral therapies, and policies to control the spread of ZIKV disease.
While ZIKV can be detected in human seminal fluid for months after the clearance of viremia,
the cellular targets and mechanisms associated with persistent infection in the testes remains
unclear. Mouse and NHP studies have recently shown that ZIKV can infect and damage the
seminiferous tubules within the testes [2-5]. The seminiferous tubules are an immune
privileged organ with a tight blood-testes barrier also known as the Sertoli-cell barrier (SCB),
which protects developing spermatozoa from peripheral pathogens and environmental toxins.
However, increased inflammatory mediators such as TNF-α and IL-1β, matrix
metalloproteinases, and cell-adhesion molecules (CAM) can disrupt the integrity of the SCB
leading to pathologic outcomes [6, 7]. Therefore, the objective of this study was to
characterize ZIKV replication kinetics and immune responses in primary human Sertoli cells
(SC) and develop an in vitro SCB model to understand mechanisms of ZIKV transmigration
across the barrier.
We demonstrate that primary human SC are highly susceptible to ZIKV as compared to the
closely related dengue virus and induced expression of IFN-α, key cytokines and celladhesion
molecules (VCAM-1 and ICAM-1). Further, using an in vitro SCB model, we show
that ZIKV was released on the adluminal side of the SCB model with higher efficiency when
compared to the blood-brain barrier model. ZIKV-infected SC also exhibited enhanced
adhesion of leukocytes that correlated with decrease in the SCB integrity. While ZIKV
infection did not affect the expression of tight and adherens junction proteins such as ZO-1,
claudin and JAM-A, exposure of SC to inflammatory mediators derived from ZIKV-infected
macrophages led to the degradation of ZO-1 protein that correlated with increased SCB
permeability. Collectively, our data suggest that infection of SC may be one of the crucial
steps by which ZIKV gains access to the site of spermatozoa development and identifies SC
as a therapeutic target. Finally, the SCB model opens up opportunities to assess interactions
of SC with other testicular cells and lays the platform for future studies to test the ability of
anti-ZIKV drugs to cross the barrier and clear testicular infection.
|Description:||M.S. Thesis. University of Hawaiʻi at Mānoa 2017.|
|Rights:||All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.|
|Appears in Collections:||
M.S. - Biomedical Sciences (Tropical Medicine)|
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