Abstract
Zika virus (ZIKV) is a unique flavivirus with high tropism to the testes. ZIKV can persist in human semen for months and can cause testicular damage in male mice. However, the mechanisms through which ZIKV enters the testes remain unclear. In this study, we revealed that matrix metalloproteinase 9 (MMP9) was upregulated by ZIKV infection in cell culture and in A129 mice. Furthermore, using an in vitro Sertoli cell barrier model and MMP9-/- mice, we found that ZIKV infection directly affected the permeability of the blood-testis barrier (BTB), and knockout or inhibition of MMP9 reduced the effects of ZIKV on the Sertoli cell BTB, highlighting its role in ZIKV-induced disruption of the BTB. Interestingly, the protein levels of MMP9 were elevated by ZIKV nonstructural protein 1 (NS1) in primary mouse Sertoli cells (mSCs) and other cell lines. Moreover, the interaction between NS1 and MMP9 induced the K63-linked polyubiquitination of MMP9, which enhanced the stability of MMP9. The upregulated MMP9 level led to the degradation of essential proteins involved in the maintenance of the BTB, such as tight junction proteins (TJPs) and type Ⅳ collagens. Collectively, we concluded that ZIKV infection promoted the expression of MMP9 which was further stabilized by NS1 induced K63-linked polyubiquitination to affect the TJPs/ type Ⅳ collagen network, thereby disrupting the BTB and facilitating ZIKV entry into the testes.
Highlights
Zika virus (ZIKV), an emerging mosquito-borne virus, belongs to the genus Flavivirus within the family Flaviviridae
We found that matrix metalloproteinase 9 (MMP9) protein levels were upregulated in sera following ZIKV infection (Fig 1G)
Consistent with this, western blotting and gelatin zymography assays revealed that ZIKV infection, detected by nonstructural protein 1 (NS1) expression, increased protein levels and gelatinase activity of MMP9 in the testes (Fig 1H), whereas MMP2 activity was not changed in infected testes, suggesting that MMP2 was constitutively expressed in vivo and was not altered by ZIKV infection
Summary
Zika virus (ZIKV), an emerging mosquito-borne virus, belongs to the genus Flavivirus within the family Flaviviridae. The first large outbreak of ZIKV spread throughout the Pacific Ocean areas to American countries in 2013–2014, affecting approximately 30,000 people, and was shown to be associated with Guillain-Barre Syndrome, a severe neurological manifestation [2, 5, 6]. ZIKV has spread to more than 84 countries worldwide [7], becoming a major public health concern. This concern has been further exacerbated by clinical evidence of potential transmission through sexual routes unique to ZIKV, in addition to mosquito bites described for other mosquito-borne flaviviruses in humans, such as dengue virus (DENV), Japanese encephalitis virus (JEV), and West Nile virus (WNV) [8]
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