Zika Virus Pathogenesis and Tissue Tropism

Abstract

Although Zika virus (ZIKV) was isolated approximately 70 years ago, few experimental studies had been published prior to 2016. The recent spread of ZIKV to countries in the Western Hemisphere is associated with reports of microcephaly, congenital malformations, and Guillain-Barré syndrome. This has resulted in ZIKV being declared a public health emergency and has greatly accelerated the pace of ZIKV research and discovery. Within a short time period, useful mouse and non-human primate disease models have been established, and pre-clinical evaluation of therapeutics and vaccines has begun. Unexpectedly, ZIKV exhibits a broad tropism and persistence in body tissues and fluids, which contributes to the clinical manifestations and epidemiology that have been observed during the current epidemic. In this Review, we highlight recent advances in our understanding of ZIKV pathogenesis, tissue tropism, and the resulting pathology and discuss areas for future investigation.

Keywords: Zika virus; congenital infection; flavivirus; host immunity; innate immunity; microcephaly; pathogenesis; tropism; viral persistence.

Figure 1. ZIKV tissue and cell tropism

Human studies and animal models (mice and non-human primates) have detected ZIKV in cells of the placenta including Hofbauer cells (in vitro and in explanted human placental tissue), trophoblasts (mice, non-human primates, and humans), and endothelial cells (in vitro in explanted human placental tissue and in vivo in placenta of mice). Other ZIKV cellular targets include neuronal cell types including neural progenitor cells and mature neurons (mice, non-human primates, and humans), and astrocytes (in vitro human cell cultures). In addition, ZIKV infects ocular tissues including the cornea, neurosensory retina, and optic nerve (mice), as well as the aqueous humor of the anterior chamber (humans). ZIKV also targets cells of the reproductive tract including spermatogonia, Sertoli cells, and Leydig cells (in the testis of mice), sperm (samples from mice and humans), and the vaginal epithelium (mice) and uterine fibroblasts (in vitro infection of human samples). The extensive tropism results in ZIKV detection in multiple body fluids including conjunctival fluid or tears (mice and humans), saliva (non-human primates and humans), semen (mice, non-human primates, and humans), cervical mucus (humans), vaginal washings (mice and human) and urine (non-human primates and humans).

Figure 2. Targets for ZIKV vaccine design

A. Highly neutralizing mouse and human anti-ZIKV monoclonal antibodies bind to distinct epitopes in the E protein including the lateral ridge of domain III (e.g., ZV-67) (Zhao et al., 2016), a domain I–III interface epitope (e.g., Z23) (Wang et al., 2016), an EDE intra-dimer epitope (e.g., C10) (Zhang et al., 2016), domain I–II and domain II intra-dimer epitopes (e.g., Z3L1 and Z20, respectively) (Wang et al., 2016), and a domain II inter-dimer epitope (e.g., ZIKV-117) (Sapparapu et al., 2016). These epitopes represent candidate regions for ZIKV vaccine design. B. Vaccine approaches that are being developed for ZIKV include DNA plasmids encoding prM-E or E genes (Abbink et al., 2016; Dowd et al., 2016b), soluble E based proteins or peptides (Alam et al., 2016), or inactivated viral particles (Abbink et al., 2016). Vaccines should generate protective B and T cell responses for greatest efficacy. Potential concerns of ZIKV vaccines that will need to be resolved prior to deployment include possible induction of Guillian-Barré syndrome or sensitizing individuals to more severe future DENV infection due to the generation of cross-reactive antibodies that promote ADE.