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; Liu, Mei; Yan, Jinghua; Li, Wei; Qin, Chuan; Han, Daishu; Qin, Chengfeng; Wang, Na; Li, Xiangdong; Gao, George F.

doi:10.1016/j.cell.2017.01.009

Cited by 85 publications

(75 citation statements)

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“…Our data showing a strong antiviral defense response to ZIKV, including the production of several inflammatory cytokines, agree with data from a recent in vitro mouse study that reported the production of TNF-␣ and IL-6 in mouse SCs but not in germ cells or peritubular myeloid cells, thus suggesting that SCs are one of the major sources of antiviral cytokines in human testes (12). Similarly, Singh and colleagues recently demonstrated that ZIKV infection of cells of the blood-retinal barrier is also associated with the production of multiple inflammatory and interferon response genes (28), suggesting that different blood-tissue barrier cells are able to mount a protective response to ZIKV.…”

Section: Discussionsupporting

confidence: 82%

“…Immunocompetent mice do not develop disease symptoms, but persistent testicular infection for up to 45 days in IFNAR1-deficient mice has been associated with proinflammatory responses, infiltration of leukocytes into the testes, and damaged architecture of the seminiferous epithelium (11,12). Similarly, nonhuman primate studies have also reported the presence of ZIKV RNA in the testes 7 to 8 days after infection (13).…”

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confidence: 93%

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Zika Virus Infects Human Sertoli Cells and Modulates the Integrity of the In Vitro Blood-Testis Barrier Model

Siemann

Strange

Maharaj

et al. 2017

J Virol

119

101

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Confirmed reports of Zika virus (ZIKV) in human seminal fluid for months after the clearance of viremia suggest the ability of ZIKV to establish persistent infection in the seminiferous tubules, an immune-privileged site in the testis protected by the blood-testis barrier, also called the Sertoli cell (SC) barrier (SCB). However, cellular targets of ZIKV in human testis and mechanisms by which the virus enters seminiferous tubules remain unclear. We demonstrate that primary human SCs were highly susceptible to ZIKV compared to the closely related dengue virus and induced the expression of alpha interferon (IFN-␣), key cytokines, and cell adhesion molecules (vascular cell adhesion molecule 1 [VCAM-1] and intracellular adhesion molecule 1 [ICAM-1]). Furthermore, using an in vitro SCB model, we show that ZIKV was released on the adluminal side of the SCB model with a higher efficiency than in the blood-brain barrier model. ZIKV-infected SCs exhibited enhanced adhesion of leukocytes that correlated with decreases in SCB integrity. ZIKV infection did not affect the expression of tight and adherens junction proteins such as ZO-1, claudin, and JAM-A; however, exposure of SCs to inflammatory mediators derived from ZIKV-infected macrophages led to the degradation of the ZO-1 protein, which correlated with increased SCB permeability. Taken together, our data suggest that infection of SCs may be one of the crucial steps by which ZIKV gains access to the site of spermatozoon development and identify SCs as a therapeutic target to clear testicular infections. The SCB model opens up opportunities to assess interactions of SCs with other testicular cells and to test the ability of anti-ZIKV drugs to cross the barrier.IMPORTANCE Recent outbreaks of ZIKV, a neglected mosquito-borne flavivirus, have identified sexual transmission as a new route of disease spread, which has not been reported for other flaviviruses. To be able to sexually transmit for months after the clearance of viremia, ZIKV must establish infection in the seminiferous tubules, the site of spermatozoon development. However, little is known about the cell types that support ZIKV infection in the human testis. Currently, there are no models to study mechanisms of virus persistence in the seminiferous tubules. We provide evidence that ZIKV infection of human Sertoli cells, which are an important component of the seminiferous tubules, is robust and induces a strong antiviral response. The use of an in vitro Sertoli cell barrier to describe how ZIKV or inflammatory mediators derived from ZIKV-infected macrophages compromise barrier integrity will enable studies to explore the interactions of other testicular cells with Sertoli cells and to test novel antivirals for clearing testicular ZIKV infection.

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 93%

Zika Virus Infects Human Sertoli Cells and Modulates the Integrity of the In Vitro Blood-Testis Barrier Model

Siemann

Strange

Maharaj

et al. 2017

J Virol

119

101

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“…ZIKV replicates in the male mouse reproductive tract (Govero et al, 2016; Rossi et al, 2016; Ma et al, 2017), is present in the seminal fluid, and can be efficiently transmitted to naïve female mice during intercourse (Duggal et al, 2017). Currently, the contribution of human sexual transmission to congenital ZIKV infection is poorly understood, but could result in an altered pathogenesis compared to mosquito-transmitted infection.…”

Section: Mechanisms and Consequences Of Maternal-fetal Transmissionmentioning

confidence: 99%

Zika in the Americas, year 2: What have we learned? What gaps remain? A report from the Global Virus Network

et al. 2017

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In response to the outbreak of Zika virus (ZIKV) infection in the Western Hemisphere and the recognition of a causal association with fetal malformations, the Global Virus Network (GVN) assembled an international taskforce of virologists to promote basic research, recommend public health measures and encourage the rapid development of vaccines, antiviral therapies and new diagnostic tests. In this article, taskforce members and other experts review what has been learned about ZIKV-induced disease in humans, its modes of transmission and the cause and nature of associated congenital manifestations. After describing the make-up of the taskforce, we summarize the emergence of ZIKV in the Americas, Africa and Asia, its spread by mosquitoes, and current control measures. We then review the spectrum of primary ZIKV-induced disease in adults and children, sites of persistent infection and sexual transmission, then examine what has been learned about maternal-fetal transmission and the congenital Zika syndrome, including knowledge obtained from studies in laboratory animals. Subsequent sections focus on vaccine development, antiviral therapeutics and new diagnostic tests. After reviewing current understanding of the mechanisms of emergence of Zika virus, we consider the likely future of the pandemic.

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“…The pathogenesis of ZIKV associated eye diseases can be studied in Ifnar1−/− 115 mice. Recently, ZIKV associated teratogenic outcomes in fetuses as well as reproductive disorders in males have been studied in mouse models [66] . Infection of pregnant Ifnar1−/− 184 C57BL/6 mice with ZIKV strain H/PF/2013 caused fetal brain injury, neuronal cell death and placental infection followed by demise [67] .…”

Section: Animal Modelsmentioning

confidence: 99%

Advances in research on Zika virus

Ali

Wahid

Rafique

et al. 2017

Asian Pacific Journal of Tropical Medicine

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Zika virus (ZIKV) is rapidly spreading across the America and its devastating outcomes for pregnant women and infants have driven this previously ignored pathogen into the limelight. Clinical manifestations are fever, joint pain or rash and conjunctivitis. Emergence of ZIKV started with a first outbreak in the Pacific area in 2007, a second large outbreak occurred in the Pacific in 2013/2014 and subsequently the virus spread in other Pacific islands. Threat of explosive global pandemic and severe clinical complications linked with the more immediate and recurrent epidemics necessitate the development of an effective vaccine. Several vaccine platforms such as DNA vaccine, recombinant subunit vaccine, ZIKV purified inactivated vaccine, and chimeric vaccines have shown potent efficacy in vitro and in vivo trials. Moreover, number of drugs such as Sofosbuvir, BCX4450, NITD008 and 7-DMA are ready to enter phase I clinical trial because of proven anti-ZIKV activity. Monoclonal based antibodies offer promise as an intervention effective for use in pregnant women. In this review, we describe the advances in research on ZIKV such as research strategies for the development of antiviral drugs & vaccines, molecular evolution, epidemiology emergence, neurological complications and other teratogenic outcomes as well as pathogenesis.

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

Cited by 85 publications

References 1 publication

Zika Virus Infects Human Sertoli Cells and Modulates the Integrity of the In Vitro Blood-Testis Barrier Model

Zika Virus Infects Human Sertoli Cells and Modulates the Integrity of the In Vitro Blood-Testis Barrier Model

Zika in the Americas, year 2: What have we learned? What gaps remain? A report from the Global Virus Network

Advances in research on Zika virus

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