Zika Virus Causes Testis Damage and Leads to Male Infertility in Mice

Ma, Wenqiang; Li, Shihua; Ma, Shuoqian; Jia, Lina; Zhang, Fuchun; Zhang, Yong; Zhang, Jingyuan; Wong, Gary; Zhang, Shanshan; Lu, Xuancheng; Mei, Linfeng; Yan, Jinghua; Li, Wei; Qin, Chuan; Han, Daishu; Qin, Cheng‐Feng; Wang, Na; Li, Xiangdong; Gao, George F.

doi:10.1016/j.cell.2016.11.016

Cited by 349 publications

(290 citation statements)

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“…Infection in the seminiferous tubules of the testis was associated with inflammatory cell infiltrates, cell death of Sertoli and male germ cells, reduced production of male sex hormones, diminished sperm counts and mobility, and decreased male fertility (42). Similar studies were performed by another group in male Ifnar1 Ϫ/Ϫ C57BL/6 mice inoculated intraperitoneally with a contemporary ZIKV strain isolated in China (43). Here, ZIKV infection also led to inflammation and injury in tissues of the male reproductive tract, including the testes and epididymis, and ZIKV infection was detected in spermatogonia and testicular peritubular-myoid cells.…”

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confidence: 54%

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Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

Morrison

Diamond

2017

J Virol

241

239

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Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that now causes epidemics affecting millions of people on multiple continents. The virus has received global attention because of some of its unusual epidemiological and clinical features, including persistent infection in the male reproductive tract and sexual transmission, an ability to cross the placenta during pregnancy and infect the developing fetus to cause congenital malformations, and its association with Guillain-Barré syndrome in adults. This past year has witnessed an intensive effort by the global scientific community to understand the biology of ZIKV and to develop pathogenesis models for the rapid testing of possible countermeasures. Here, we review the recent advances in and utility and limitations of newly developed mouse and nonhuman primate models of ZIKV infection and pathogenesis.

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confidence: 54%

“…Recently, mouse models have investigated the consequences of ZIKV infection in the male reproductive tract (42,43). In one of these studies, male WT C57BL/6 mice were treated with a single dose of a blocking anti-IFNAR1 MAb, followed by subcutaneous inoculation of a mouse-adapted African strain (Dakar 41519) of ZIKV (42).…”

mentioning

confidence: 99%

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

Morrison

Diamond

2017

J Virol

241

239

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“…Significant outbreaks of ZIKV, a re-emerging mosquito-borne flavivirus, have occurred worldwide since 2013 [1,2]. Importantly, ZIKV infection has led to a global crisis due to its unexpected links to testis damage [3,4], ocular damage [5,6], Guillain-Barre syndrome, fetal microcephaly [1,[7][8][9], and potentially to other neural complications [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

et al. 2017

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Recent outbreaks of Zika virus (ZIKV) highlight an urgent need for therapeutics.The protease complex NS2B-NS3 plays essential roles during flaviviral polyprotein processing, and thus represents an attractive drug target. Here, we developed a split luciferase complementation-based high-throughput screening assay to identify orthosteric inhibitors that directly target flavivirus NS2B-NS3 interactions. By screening a total of 2 816 approved and investigational drugs, we identified three potent candidates, temoporfin, niclosamide, and nitazoxanide, as flavivirus NS2B-NS3 interaction inhibitors with nanomolar potencies. Significantly, the most potent compound, temoporfin, not only inhibited ZIKV replication in human placental and neural progenitor cells, but also prevented ZIKV-induced viremia and mortality in mouse models. Structural docking suggests that temoporfin potentially binds NS3 pockets that hold critical NS2B residues, thus inhibiting flaviviral polyprotein processing in a non-competitive manner. As these drugs have already been approved for clinical use in other indications either in the USA or other countries, they represent promising and easily developed therapies for the management of infections by ZIKV and other flaviviruses.

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“…[10] In adult men, ZV keeps on shedding in semen for more than two months after infection and damages spermatogonia in male reproductive organs resulting in male infertility. [19] Therefore, the consequences of ZV epidemic are affecting next human generations.…”

Section: Transmissionmentioning

confidence: 99%

Recent Advances in Zika Virus Vaccine Development

Shafique¹

2017

IJVR

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Figure 1: Three different mechanisms of ADE (Antibody-dependent enhancement):A-receptors on virus particles bound by cross-reactive antibody get conformational change in structure that results in high affinity with the corresponding receptor on the host cell membrane. The corresponding receptor was not able to recognize the viral receptor before this conformational change. B-The cross-reactive antibody binds to viral and host cell membrane receptors at the same time bringing the viral particle near to the host cell. C-The Fc component of the cross-reactive antibody is recognized by the corresponding receptor on host cell membrane being the predominant mechanism of ADE phenomenon. [DENV], are the primary focus for the current vaccine and therapeutic research against ZV. Zika virus spreads by a mosquito, Anopheles Aegypti. [16] In addition to the mosquito bite, the vertical transmission, from mother to baby during pregnancy, and the sexual transmission have also been reported. Transmission[25] ZV infection is characterized by mild rash and fever.[22] However, where it infects the cells of nervous system may result in severe non-reversible complications. The neurological complications include Guillain-Barre (GB) syndrome characterized by neuromuscular paralysis .[24] ZV infection during pregnancy causes Congenital Zika Virus syndrome (CZS) which is a defined set of congenital conditions in newborns. CZS consists of microcephaly, decreased brain tissue, damage to the back of the eye, joints with limited movement and increased muscle tone . [7] Microcephaly, where the head circumference of newborn is less than thirty-two cms, has been the hallmark of the teratogenicity of ZV maternal infection.[2] ZV infection in pregnancy complicated with the microcephalic baby is a major cause of the anxiety and depression among the reproductive age women of ZV endemic area.[10] In adult men, ZV keeps on shedding in semen for more than two months after infection and damages spermatogonia in male reproductive organs resulting in male infertility.[19] Therefore, the consequences of ZV epidemic are affecting next human generations.The phenomenon of Antibody Dependent Enhancement of infection (ADE) is an important risk for the sample selection in clinical trials for monoclonal antibodies. Antibody Dependent Enhancement of infection is the phenomenon that results in magnifying the host cell infection by the viruses of same family due to the presence of cross-reactive antibodies. The respective antibodies recognize the receptors on the viral particle and the host cell membrane. These antibodies may be produced against one type of virus, for example Dengue Virus and can cross-react with the same epitopes present on the Zika Virus (ZV). There are three proposed mechanisms of ' ADE, the first one being recognition of the receptor on the surface of virus particle, inducing a conformational change in the structure of the receptor that increases its affinity for a corresponding receptor on the host cell membrane (Figure 1 A). In the second me...

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Zika Virus Causes Testis Damage and Leads to Male Infertility in Mice

Cited by 349 publications

References 49 publications

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

Recent Advances in Zika Virus Vaccine Development

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