Zebrafish: Modeling for Herpes Simplex Virus Infections

Abstract

For many years, zebrafish have been the prototypical model for studies in developmental biology. In recent years, zebrafish has emerged as a powerful model system to study infectious diseases, including viral infections. Experiments conducted with herpes simplex virus type-1 in adult zebrafish or in embryo models are encouraging as they establish proof of concept with viral-host tropism and possible screening of antiviral compounds. In addition, the presence of human homologs of viral entry receptors in zebrafish such as 3-O sulfated heparan sulfate, nectins, and tumor necrosis factor receptor superfamily member 14-like receptor bring strong rationale for virologists to test their in vivo significance in viral entry in a zebrafish model and compare the structure-function basis of virus zebrafish receptor interaction for viral entry. On the other end, a zebrafish model is already being used for studying inflammation and angiogenesis, with or without genetic manipulations, and therefore can be exploited to study viral infection-associated pathologies. The major advantage with zebrafish is low cost, easy breeding and maintenance, rapid lifecycle, and a transparent nature, which allows visualizing dissemination of fluorescently labeled virus infection in real time either at a localized region or the whole body. Further, the availability of multiple transgenic lines that express fluorescently tagged immune cells for in vivo imaging of virus infected animals is extremely attractive. In addition, a fully developed immune system and potential for receptor-specific knockouts further advocate the use of zebrafish as a new tool to study viral infections. In this review, we focus on expanding the potential of zebrafish model system in understanding human infectious diseases and future benefits.

Comprehensive Analysis of Herpes Simplex Virus 1 (HSV-1) Entry Mediated by Zebrafish 3- O -Sulfotransferase Isoforms: Implications for the Development of a Zebrafish Model of HSV-1 Infection

“…3E and F). Taken together, our current findings suggest that the ZF 3-OST-6 isoform, but not 3-OST-1, -5, and -7, mediates HSV-1 entry and cell fusion in a manner similar to that of the previously reported ZF 3-OST isoforms (3-OST-2, -3, and -4) (14)(15)(16)(17). Therefore, based on the ZF 3-OST gene characterizations for HSV-1 entry, we categorize them into two groups, in which group I (3-OST-2, -3, -4, and -6) allows HSV entry, while group II (3-OST-1, -5, and -7) does not generate a gD receptor; hence, cells expressing the latter 3-OST isoforms are not susceptible to HSV-1 entry (Fig.…”

“…These ZF enzyme isoforms are differentially expressed in a tissue-specific manner, suggesting the possibility of creating a tool to study HSV tissuespecific tropism, whose study is hampered by the lack of available convenient tools. Our previous preliminary studies suggested that ZF 3-OST may mediate HSV entry (15). In this study, we investigated the ability of ZF 3-OST-1, -5, -6, and -7 isoforms, comparatively to their human analogue, to facilitate HSV-1 entry and cell-cell fusion.…”

“…Recent studies of zebrafish (ZF) provided a functional analysis of 3-OST-generated HS (11)(12)(13)(14)(15). Out of the characterized eight 3-OST family members in ZF, seven genes show homology to known 3-OST genes in mice and humans (11).…”

Studying the immune response to human viral infections using zebrafish

“…The first reported human pathogens that could infect and cause disease in zebrafish were bacteria (reviewed in Trede et al, 2004; van der Sar et al, 2004; Phelps and Neely, 2005; Sullivan and Kim, 2008; Meijer and Spaink, 2011; Milligan-Myhre et al, 2011; Novoa and Figueras, 2011). There are now reports of zebrafish models of human fungal (Chao et al, 2010; Brothers et al, 2011; Brothers et al, 2013; Chen et al, 2013; Gratacap et al, 2013; Kuo et al, 2013; Y.-C. Wang et al, 2013) and human viral pathogen infections (Burgos et al, 2008; Ding et al, 2011; Antoine et al, 2013; Palha et al, 2013; K. A. Gabor and C. H. Kim, personal communication). We will describe the human viral illnesses for which there are currently zebrafish infection models and then discuss the findings and insights obtained thus far from these zebrafish models of human viral infections.…”

Conservation of the STING-Mediated Cytosolic DNA Sensing Pathway in Zebrafish

“…HSV-1 infection has been extensively employed to elucidate STING signaling in mice (25,37). Some preliminary studies suggested that HSV-1 could potentially infect zebrafish and persist in adult zebrafish brain (13,38). It remains unknown whether HSV-1 infection could be adapted to explore cytosolic DNA signaling in zebrafish.…”