Under attack: Modulation of the blood-testes barrier by Zika virus

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Abstract The 2015-2016 epidemic of Zika virus (ZIKV) has caused severe unexpected clinical outcomes including microcephaly and Guillain-Barre Syndrome. ZIKV is primarily a mosquito-transmitted virus but the concerns regarding sexual transmission has gained urgency as the alarming increase in the number of cases of microcephaly in ZIKV-infected women coincided with the detection of the virus in the semen. Association of ZIKV with hematospermia and presence of infectious ZIKV in the semen when viremia is undetectable in humans suggest the ability of ZIKV to establish infection in the testes. Lack of any vaccine or specific therapeutic drugs to combat ZIKV infection and prevent testicular infection has brought an urgent need for the development of in vitro systems and in vivo models to understand the associated mechanisms. Seminiferous tubules, the site of spermatogenesis within the testes, is an immune privileged site with an effective blood-testes barrier (BTB) that prevents microbial infections and protects immunogenic germ cells from systemic immune attack. The BTB, constituted exclusively by specialized tight junctions proteins (TJP) between the adjacent sertoli cells (SC) provides physical and immunological barrier to the seminiferous tubules. Increased production of inflammatory mediators such as TNF-α, IL-8, matrix metalloproteinases (MMPs) and cell-adhesion molecules (CAM) has been suggested to disrupt BTB and facilitate testicular infections. Although, compelling data from recent studies suggest that ZIKV has the ability to infect testes that may allow escape from immune detection, little is known about ZIKV infection of the testes. This proposal seeks to determine the mechanisms of ZIKV entry into the testes by utilizing an in vitro BTB model system using primary human SC and in vivo nonhuman primate model. We will address the hypothesis that to remain infectious in the testes even after the virus is cleared from the periphery, ZIKV infects SC and testes macrophages to induce inflammatory response that alters the expression of TJP, leading to BTB disruption and allowing entry of the virus into the seminiferous tubules thus establishing persistent infection in the testes. Our group is uniquely positioned to delineate the mechanisms of ZIKV testicular entry because of our previous experience of utilizing in vitro blood-brain barrier system and in vivo models to study WNV-neuroinvasion mechanisms. The specific aim 1 will determine how cell-free and macrophage-associated ZIKV transmigrates across the human in vitro BTB model and affects the barrier integrity. We will also assess if the induction of inflammatory mediators including cytokines, MMPs and CAM by ZIKV can affect expression of multiple TJP and BTB integrity. Specific Aim 2 will evaluate whether ZIKV affects the BTB integrity in the experimentally infected macaques and determine the relationship with persistence of virus and inflammatory and antiviral response in the testes. It is anticipated that the integration of data from the in vitro human system and highly relevant NHP model will fill the fundamental gap of the mechanism of ZIKV-testes entry and enhance our understanding of the specific immune response to testicular virus infection. Together this information may guide future strategies to manipulate the system for the development of novel approaches to eradicate virus from the testes.