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Review
. 2018 Apr;153(4):443-454.
doi: 10.1111/imm.12883. Epub 2018 Jan 19.

Using immunocompromised mice to identify mechanisms of Zika virus transmission and pathogenesis

Clayton W Winkler  1 , Karin E Peterson  1
Affiliations
Review

Using immunocompromised mice to identify mechanisms of Zika virus transmission and pathogenesis

Clayton W Winkler et al. Immunology. 2018 Apr.

Abstract

Zika virus (ZIKV) is responsible for a recent global epidemic that has been associated with congenital brain malformations in fetuses and with Guillain-Barré syndrome in adults. Within the last 2 years, a major effort has been made to develop murine models to study the mechanism of viral transmission, pathogenesis and the host immune response. Here, we discuss the findings from these models regarding the role that the innate and adaptive immune responses have in controlling ZIKV infection and pathogenesis. Additionally, we examine how innate and adaptive immune responses influence sexual and vertical transmission of ZIKV infection as well as how these responses can influence the ability of ZIKV to cross the placenta and to induce damage in the developing brain.

Keywords: T cell; innate receptors; neuroinflammation; reproductive Immunology; viral.

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Figures

Figure 1
Figure 1
Immune responses to Zika virus (ZIKV) are critical to prevent pathogenesis and transmission but may also contribute to autoimmunity. (a) Models of ZIKV infection in mice have demonstrated that elements of the innate immune response are critical for preventing infection of the testes in males. Experiments with mice deficient in innate immune signalling have shown testicular pathology and prolonged infection of cells in the testes, including sperm, which allow for animal‐to‐animal sexual transmission of ZIKV. These models are reminiscent of findings in humans. (b) Additionally, sexual transmission or intravaginal inoculation of mice demonstrates that the female reproductive tract is permissive to ZIKV infection. Furthermore, these modes of transmission in mice deficient in innate immune signalling can result in ZIKV‐associated disease and vertical transmission to fetuses. (c) In mice with innate immune signalling deficiencies, ZIKV can infect peripheral nerves within the dorsal root ganglia. Such an infection could induce an autoimmune response reminiscent of Guillain–Barré syndrome, which in humans is associated with ZIKV infection. TC, T cell; Ig, immunoglobulin.
Figure 2
Figure 2
Zika virus (ZIKV) vertical transmission has been demonstrated in murine models, but further study is required to determine the specific mechanism of transmission. (a) In both mice and humans, the developing fetus and placenta are separated from the maternal myometrium by the decidua and the trophoblast giant cell layer. The placenta serves as the primary interface between the fetal and maternal blood where nutrient exchange occurs. In several mouse vertical transmission models, ZIKV has been shown to heavily infect the placenta. If infection occurs early in development, fetuses typically are reabsorbed or are not viable at birth. Infection later in development can result in vertical transmission and infection of the fetal brain and lymphatic tissue. (b) Vertical transmission in mice can occur if virus is inoculated intravaginally or through a peripheral route and is not necessary transmitted to all fetuses in a litter. Further experimentation with these models is required to determine the rate and timing of transmission. (c) ZIKV must cross the placental barrier, which is formed by syncytiotrophoblasts (STC), in order to be vertically transmitted. Multiple crossing mechanisms are possible. These include damage to STC cells by maternal or fetal immune cells, antibody‐dependent viral transcytosis, infection of maternal immune cells that cross the STC and or infection of HCs that cross back into fetal blood. FEC, fetal endothelial cells, BM, basement membrane, HC, Hoffbauer cells, DC, dendritic cells, MO/iMO, monocyte/macrophage, fRBCs, fetal red blood cells, MTC, mononuclear trophoblast cell, STC, syncytiotrophoblast cells.
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