Modelling viral encephalitis caused by herpes simplex virus 1 infection in cerebral organoids.

Herpes simplex encephalitis is a life-threatening disease of the central nervous system caused by herpes simplex viruses (HSVs). Following standard of care with antiviral acyclovir treatment, most patients still experience various neurological sequelae. Here we characterize HSV-1 infection of human brain organoids by combining single-cell RNA sequencing, electrophysiology and immunostaining. We observed strong perturbations of tissue integrity, neuronal function and cellular transcriptomes. Under acyclovir treatment viral replication was stopped, but did not prevent HSV-1-driven defects such as damage of neuronal processes and neuroepithelium. Unbiased analysis of pathways deregulated upon infection revealed tumour necrosis factor activation as a potential causal factor. Combination of anti-inflammatory drugs such as necrostatin-1 or bardoxolone methyl with antiviral treatment prevented the damages caused by infection, indicating that tuning the inflammatory response in acute infection may improve current therapeutic strategies.

Human disease models in drug development.

Biomedical research is undergoing a paradigm shift towards approaches centred on human disease models owing to the notoriously high failure rates of the current drug development process. Major drivers for this transition are the limitations of animal models, which, despite remaining the gold standard in basic and preclinical research, suffer from interspecies differences and poor prediction of human physiological and pathological conditions. To bridge this translational gap, bioengineered human disease models with high clinical mimicry are being developed. In this Review, we discuss preclinical and clinical studies that benefited from these models, focusing on organoids, bioengineered tissue models and organs-on-chips. Furthermore, we provide a high-level design framework to facilitate clinical translation and accelerate drug development using bioengineered human disease models.

Histological and functional comparisons of four anatomical regions of porcine skin with human abdominal skin.

Because of the shortage of human skin for research purposes, porcine skin has been used as a model of human skin. The aim of this study was to identify the region of German Landrace pig skin that could be used as the best possible substitute for human abdominal skin. Porcine samples were collected from the ear, flank, back and caudal abdomen; human abdominal skin samples were excised during plastic surgery. Histological and ultrastructural assessments were carried out on the epidermis and dermis, with emphasis on the dermo-epidermal interface length, dermo-epidermal thickness ratio as well as densities of; hair follicles, arrector pili muscles, blood vessels and sweat glands. In the pig, the barrier function of the four anatomical regions was assessed. Results showed that both histologically and ultrastructurally, all four regions of porcine skin were similar to human skin. These include the shapes of keratinocytes, structure of cell contacts and presence of Weibel Palade bodies in endothelial cells. Other parameters such as the thickness of epidermis, the thickness of stratum basale, spinosum and granulosum and the number of cell layers in the stratum corneum were similar in human abdominal and in all four regions of porcine skin. However, there were also significant differences especially in the thickness of the stratum corneum, the dermo-epidermal interface length and the blood vessel density.

Diversity of parvovirus 4-like viruses in humans, chimpanzees, and monkeys in hunter-prey relationships.

During 2010-2011, we investigated interspecies transmission of partetraviruses between predators (humans and chimpanzees) and their prey (colobus monkeys) in Côte d'Ivoire. Despite widespread infection in all species investigated, no interspecies transmission could be detected by PCR and genome analysis. All sequences identified formed species- or subspecies (chimpanzee)-specific clusters, which supports a co-evolution hypothesis.