Pathogenesis and Manifestations of Zika Virus-Associated Ocular Diseases

Abstract

Zika virus (ZIKV) is mosquito-borne flavivirus that caused a significant public health concern in French Polynesia and South America. The two major complications that gained the most media attention during the ZIKV outbreak were Guillain-Barré syndrome (GBS) and microcephaly in newborn infants. The two modes of ZIKV transmission are the vector-borne and non-vector borne modes of transmission. Aedes aegypti and Aedes albopictus are the most important vectors of ZIKV. ZIKV binds to surface receptors on permissive cells that support infection and replication, such as neural progenitor cells, dendritic cells, dermal fibroblasts, retinal pigment epithelial cells, endothelial cells, macrophages, epidermal keratinocytes, and trophoblasts to cause infection. The innate immune response to ZIKV infection is mediated by interferons and natural killer cells, whereas the adaptive immune response is mediated by CD8⁺T cells, Th1 cells, and neutralizing antibodies. The non-structural proteins of ZIKV, such as non-structural protein 5, are involved in the evasion of the host's immune defense mechanisms. Ocular manifestations of ZIKV arise from the virus' ability to cross both the blood-brain barrier and blood-retinal barrier, as well as the blood-aqueous barrier. Most notably, this results in the development of GBS, a rare neurological complication in acute ZIKV infection. This can yield ocular symptoms and signs. Additionally, infants to whom ZIKV is transmitted congenitally develop congenital Zika syndrome (CZS). The ocular manifestations are widely variable, and include nonpurulent conjunctivitis, anterior uveitis, keratitis, trabeculitis, congenital glaucoma, microphthalmia, hypoplastic optic disc, and optic nerve pallor. There are currently no FDA approved therapeutic agents for treating ZIKV infections and, as such, a meticulous ocular examination is an important aspect of the diagnosis. This review utilized several published articles regarding the ocular findings of ZIKV, antiviral immune responses to ZIKV infection, and the pathogenesis of ocular manifestations in individuals with ZIKV infection. This review summarizes the current knowledge on the viral immunology of ZIKV, interactions between ZIKV and the host's immune defense mechanism, pathological mechanisms, as well as anterior and posterior segment findings associated with ZIKV infection.

Keywords: Zika virus; anterior uveitis; chorioretinitis; conjunctivitis; glaucoma; infectious disease; virology.

Figure 1

Ocular manifestations of Zika virus infection.

Figure 2

TLR3-mediated innate immune response yields type I IFN and proinflammatory mediators. The RIG-I/MDA5 signaling pathway generates type I IFN, type III IFN, and proinflammatory mediators. TLR3: Toll-like receptor 3; RIG-I: retinoic acid-inducible gene I; MDA5: melanoma differentiation-associated gene 5; MAVS: mitochondria antiviral signaling; TIR: toll/interleukin-1 receptor; TRIF: TIR-domain-containing adapter-inducing interferon-β; TRAF3: tumor necrosis factor receptor associated factor 3; TRAF6: tumor necrosis factor receptor associated factor 6; TBK1: TANK-binding kinase 1; IKK: Inhibitory kappaB kinase; IRF3/7: Interferon regulatory factor 3/7; IRF3: Interferon regulatory factor 3; NF-κB: nuclear factor-kappaB; Type I IFN: Type I interferon; Type III IFN: type III interferon.

Figure 3

IFNα/β generates the antiviral response to control ZIKV infection. IFNα: Interferon alpha; IFNβ: Interferon beta; IFNAR1: interferon alpha receptor 1; IFNAR2: interferon alpha receptor 2; TYK2: Tyrosine kinase 2; JAK1: Janus activated kinase 1; STAT1: signal transducer and activator of transcription 1; STAT2: signal transducer and activator of transcription 2; IRF9: interferon regulatory factor 9; ISG: Interferon-stimulated genes.