Implications of TORCH Diseases in Retinal Development-Special Focus on Congenital Toxoplasmosis

Abstract

There are certain critical periods during pregnancy when the fetus is at high risk for exposure to teratogens. Some microorganisms, including Toxoplasma gondii, are known to exhibit teratogenic effects, interfering with fetal development and causing irreversible disturbances. T. gondii is an obligate intracellular parasite and the etiological agent of Toxoplasmosis, a zoonosis that affects one third of the world's population. Although congenital infection can cause severe fetal damage, the injury extension depends on the gestational period of infection, among other factors, like parasite genotype and host immunity. This parasite invades the Central Nervous System (CNS), forming tissue cysts, and can interfere with neurodevelopment, leading to frequent neurological abnormalities associated with T. gondii infection. Therefore, T. gondii is included in the TORCH complex of infectious diseases that may lead to neurological malformations (Toxoplasmosis, Others, Rubella, Cytomegalovirus, and Herpes). The retina is part of CNS, as it is derived from the diencephalon. Except for astrocytes and microglia, retinal cells originate from multipotent neural progenitors. After cell cycle exit, cells migrate to specific layers, undergo morphological and neurochemical differentiation, form synapses and establish their circuits. The retina is organized in nuclear layers intercalated by plexus, responsible for translating and preprocessing light stimuli and for sending this information to the brain visual nuclei for image perception. Ocular toxoplasmosis (OT) is a very debilitating condition and may present high severity in areas in which virulent strains are found. However, little is known about the effect of congenital infection on the biology of retinal progenitors/ immature cells and how this infection may affect the development of this tissue. In this context, this study reviews the effects that congenital infections may cause to the developing retina and the cellular and molecular aspects of these diseases, with special focus on congenital OT.

Keywords: TORCH; Toxoplasma gondii; congenital infections; congenital toxoplasmosis; retinal development; teratogenesis.

Figure 1

Schematic organization of the vertebrate retina. (Left) Vertical section of mouse retina labeled with nuclear marker DAPI revealing the organization of the retina in layers of cell bodies and process named as follows: ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), and inner/outer segment of photoreceptors (IS/OS). (Right) The retina consists of different cell types located in specific layers. Cell bodies of rod and cone photoreceptors (brown) are located in the ONL. Both photoreceptors perform synapses in the OPL with bipolar (purple) and horizontal (lilac) cells, which, in turn, show the cell bodies in the outer portion of INL, as well as amacrine (yellow) cells and Müller (blue) cells. Bipolar and amacrine cells arborize in the IPL, contacting ganglion cell dendrites. Rod bipolar cells arborizes in the inner portion of IPL. Cone bipolar cells (right pair of purple cells) are subdivided in ON and OFF bipolar cell contacting the same cone in the OPL and synapsing, respectively, in the ON (b) or OFF portion of the IPL [dashed line shows the functional division of the IPL in OFF (a) and ON (b) circuitries. Ganglion (orange), as well as displaced amacrine (dA) cell bodies are situated in the GCL. Axons of ganglion cells form the nerve fiber layer (NFL), leave the retina through the optic head nerve taking the information to visual brain nuclei by optic nerve (ON). The three types of glial cells (Müller, astrocytes, and microglia) are found in different retinal layers. Astrocytes (green) are restricted to the inner portion of the retina, in the NFL and GCL, and have a close relation to blood vessels. Microglia (dark purple) appear preferentially in the plexiform layers (IPL and OPL). Finally, Müller cells, the predominant glia in the retina, extend their processes radially throughout the retina forming the inner limiting membrane (ILM) and the outer limiting membrane (OLM). Muller glia processes interacts with almost all retinal cell types, including blood vessels, displaying a crucial role in the physiology of this tissue. In mice and humans, the inner retina is vascularized by three capillary branches of central retinal artery. The outer retina, with the avascular photoreceptor region, relies on the choriocapillaris (Ch) lying beneath the retinal pigment epithelium (RPE)]. Scale bar: 20 μm.

Figure 2

Time course of retinal neurogenesis in human and mice. There are two main waves of retinal cell birth from early and late progenitors. The first wave begins around embryonic day (E) 10–18 in mice and gestational week (GW) 6–18 in humans, with ganglion (dark blue) cells being the first cell type to exit the cell cycle, followed by horizontal (purple), cone photoreceptors (green), and amacrine cells (yellow line). Late progenitors generate rod photoreceptors (magenta line) from E12/GW6, bipolar cells (red line) from E16/GW14 and Müller glial cells (light blue) from E18/GW18 until P7/GW30.

Figure 3

Main eye structures affected by each TORCH agent during development (indicated by colored circles). Clinical consequences regarding congenital T. gondii (green symbols), Herpes simplex virus (blue), Rubella virus (magenta), Zika Virus (orange), and Cytomegalovirus (navy blue) infection are listed besides each pathogen's name. Viral structure representations were based on Hulo et al. (2011).