*2.2.1 Ocular complications from Zika virus infections*

The endemic emergence of Zika virus (ZIKV in various regions of the planet) has been accompanied by an unprecedented increase in the spectrum of ZIKV-associated diseases. It is becoming increasingly clear that ZIKV infection has implications that go beyond microcephaly, as infants born with congenital ZIKV have pathologies that also affect the eyes, ears, limbs, and possibly other organs [27]. Consequently, there has been a growing interest in understanding the pathogenesis of ZIKV in neurological diseases.

Since clinical studies have linked ZIKV to ocular abnormalities, mainly in the retina of infants and adults [28, 29] and to uveitis in children [30, 31]; for these reasons, it is important to study the pathogenesis of ZIKV in the eye to identify potential targets for therapeutic intervention since this virus currently has no effective vaccine.

## **Figure 2.**

*Symptomatology attributable to Zika virus infection.*

## *Nutraceutical Approach for the Treatment of Retinal Inflammation after Infections DOI: http://dx.doi.org/10.5772/intechopen.105687*

It has been shown that direct inoculation of ZIKV into the eye of an adult mouse causes retinal lesions with signs (chorioretinal atrophy and mottling of the RPE) that resemble of the ZIKV-associated ocular pathology described in humans. It has also been observed that ZIKV infects different retinal cell types and stimulates an innate antiviral response in the retina.

The main protective mechanism that controls the influx of innate immune cells and pathogens into the posterior segment of the eye is the presence of the bloodretinal barrier (BRB), consisting internally of retinal vascular endothelial cells and externally of RPE cells [32]. BRB dysfunction is known to allow infectious agents to enter the retina and cause inflammation and tissue damage [33].

The study by Kumar Singh and coworkers [34] shows that ZIKV has the ability to induce the expression of TLR3, RIGI, and MDA5 in RPE, HRvECs, and in the retina, suggesting that these PRRs might be involved in ZIKV recognition in the eye. Activation of PRRs leads to the production of various inflammatory mediators, including cytokines, chemokines, and IFNs both in vitro and in vivo. In this study, it was also shown that direct inoculation of ZIKV has the ability to create retinal lesions in adult WT mice, with evidence of choroidal inflammation, activation of antiviral innate immune response, and damage with atrophy and death of the RPE. The limitation of this study, in the in vivo experiments, was the intravitreal inoculation method, which itself bypasses the BRB and directly infects retinal cell types (**Figure 3**).

A further study investigated the potential mechanisms of ZIKV-induced degeneration by going to analyze retinal inflammation and endoplasmic reticulum (ER) stress in retinas at p8, a stage when the retinal tissue is still developing. The authors of this study [35] demonstrate how ZIKV-infected retinas are morphologically damaged compared with control retinas (**Figure 4**) and found that the levels of several key inflammatory molecules including chemokines (CCL2 and CXCL10), pro-inflammatory cytokines (TNFα, IL-1β, and IL-6), adhesion molecules (ICAM-1 and VCL-1), and iNOS were increased by 1.6–1300-fold in ZIKV-infected retinas. Similarly, key

**Figure 4.** *Retinal degeneration induced by ZIKV infection. The image was modified from Li et al. [35].*

molecules involved in ER stress, including XBP1s, GRP78, and CHOP, were significantly increased. Furthermore, in association with the increase in inflammation and ER stress, levels of cleaved caspase 3, a marker of apoptosis, and phosphorylated receptor-interacting protein 3 (pRIP3), a marker of necroptosis, were also increased in ZIKV-infected retinas. The cells most affected by this infection appeared to be localized mainly in the INL, where cleaved caspase 3-positive cells were visible, and in the IPL and GCL where pRIP3-positive cells were localized (**Figure 5**). These results

## **Figure 5.**

*Localization of key markers of apoptosis (green, cleaved caspase 3) and necroptosis (green, pRIP3) in ZIKVinfected retinas. The image was modified from Li et al. [35].*

## *Nutraceutical Approach for the Treatment of Retinal Inflammation after Infections DOI: http://dx.doi.org/10.5772/intechopen.105687*

suggest that ZIKV-induced retinal degeneration may involve inflammation and ER stress by mediating cell apoptosis and necroptosis.

All of the evidence reported in the various studies concurs in suggesting that ZIKV infection leads to degeneration that can be likened to AMD-like degeneration where processes of chronic inflammation drive the progression of the disease. To date, however, it is not possible to permanently prevents this type of infection because there is no effective vaccine available, so one of the possible strategies to counteract ZIKV-induced chronic inflammation could be to use anti-inflammatory molecules. To this end, possible anti-inflammatory approaches through the use of nutraceutical molecules will be reported in the next section.
