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People infected with the mosquito-borne Rift Valley fever virus (RVFV) can suffer from eye-related problems resulting in ongoing vision issues or even permanent blindness. Despite ocular disease being the most frequently reported severe outcome, it is vastly understudied compared to other disease outcomes caused by RVFV. Ocular manifestations of RVFV include blurred vision, uveitis, and retinitis. When an infected individual develops macular or paramacular lesions, there is a 50% chance of permanent vision loss in one or both eyes. The cause of blinding ocular pathology remains unknown in part due to the lack of a tractable animal model. Using 3 relevant exposure routes, both subcutaneous (SC) and aerosol inoculation of Sprague Dawley rats led to RVFV infection of the eye. Surprisingly, direct inoculation of the conjunctiva did not result in successful ocular infection. The posterior segment of the eye, including the optic nerve, choroid, ciliary body, and retina, were all positive for RVFV antigen in SC-infected rats, and live virus was isolated from the eyes. Proinflammatory cytokines and increased leukocyte counts were also found in the eyes of infected rats. Additionally, human ocular cell lines were permissive for Lrp1-dependent RVFV infection. This study experimentally defines viral tropism of RVFV in the posterior segment of the rat eye and characterizes virally-mediated ocular inflammation, providing a foundation for evaluation of vaccines and therapeutics to protect against adverse ocular outcomes.

Rift Valley fever (RVF) is a disease of animals and humans associated with abortions in ruminants and, more recently, late-gestation miscarriages in African women. Here, we use a rat model of congenital RVF to identify cellular tropism, pathology, and local immune responses occurring in the placenta during vertical transmission. Infection of pregnant rats during late gestation (embryonic day 14) resulted in vertical transmission to the placenta and widespread viral infection throughout the decidua, basal zone, and labyrinth zone. Some pups delivered from infected dams appeared normal while others had gross signs of teratogenicity including fetal death. Histopathological lesions were detected in placenta from pups regardless of teratogenicity, while teratogenic pups had more widespread hemorrhage throughout multiple placenta layers. Teratogenic events were also associated with significant increases in pro-inflammatory cytokines, type I interferons, and chemokines within the placental tissue. Thus, we found that RVFV displays a high degree of tropism for all placental tissue layers, and that the degree of hemorrhage and inflammatory mediator production is highest in placenta from pups with adverse outcomes. This is the first detailed pathological study of the mechanisms of RVFV infection of placental tissue in a tractable rodent model of congenital RVF disease.

Background Drug repurposing is a cost-effective strategy to identify drugs with novel effects. We searched for drugs exhibiting inhibitory activity to Herpes Simplex virus 1 (HSV-1). Our strategy utilized gene expression data generated from HSV-1-infected cell cultures which was paired with drug effects on gene expression. Gene expression data from HSV-1 infected and uninfected neurons were analyzed using BaseSpace Correlation Engine (Illumina®). Based on the general Signature Reversing Principle (SRP), we hypothesized that the effects of candidate antiviral drugs on gene expression would be diametrically opposite (negatively correlated) to those effects induced by HSV-1 infection. Results We initially identified compounds capable of inducing changes in gene expression opposite to those which were consequent to HSV-1 infection. The most promising negatively correlated drugs (Valproic acid, Vorinostat) did not significantly inhibit HSV-1 infection further in African green monkey kidney epithelial cells (Vero cells). Next, we tested Sulforaphane and Menadione which showed effects similar to those caused by viral infections (positively correlated). Intriguingly, Sulforaphane caused a modest but significant inhibition of HSV-1 infection in Vero cells (IC50 = 180.4 µM, p = 0.008), but exhibited toxicity when further explored in human neuronal progenitor cells (NPCs) derived from induced pluripotent stem cells. Conclusions These results reveal the limits of the commonly used SRP strategy when applied to the identification of novel antiviral drugs and highlight the necessity to refine the SRP strategy to increase its utility.

Herpes simplex virus, type 1 (HSV-1) infection is highly prevalent and globally affects approximately 67% of people under age 50. It causes substantial morbidity, including recurrent ocular disease, cold sores, and rare cases of devastating encephalitis. Its pathogenicity stems primarily from the ability of the virus to cause recurrent lytic lesions, a consequence of its ability to persist for life as a latent infection in neurons. Latency is an elusive, poorly understood, and to date, untreatable process that involves a dynamic interplay between the virus and host cells. While considerable knowledge of the HSV-1 latent state has been gleaned from small animal modeling, we are now at the cusp of needing to examine HSV-1 in more human relevant models, as HSV-1 is a human-specific virus, and the underlying mechanisms of latency have presumably evolved over millennia through human host–virus interactions. Neuron-virus studies have been substantially hampered by the absence of satisfactory human models. Human induced pluripotent stem cell (hiPSC) and embryonic stem cell (hESC) technologies are profoundly changing this picture, as they can provide human neuron models to examine the interaction of pathogens with their hosts. They are also aiding in the development of novel therapeutic approaches. Herein, we describe the use of hiPSCs to derive human models of HSV-1 acute and latent infections and to generate human neuronal platforms for antiviral drug screening.