The skin is a multilayered organ acting as barrier against external threats, including viruses. Part of this protection is conferred by the broad variety of immune cells compartmentalized in the different skin layers. Amongst these cells, macrophages are key players in skin immunosurveillance and homeostasis under physiological and inflammatory conditions. Recently, a subset of these cells has been described in close contact to sensory neurons innervating the skin, ensuring sensory neuron repair upon wound healing. Infections by arboviruses, delivered to the skin by blood-feeding arthropods, are a rising cause of concern for global health. Of note, arboviruses can cause nervous disorders, either from direct infection of neurons or as a consequence of systemic inflammation. Interactions between arboviruses and the cell types present in the skin likely play a key role in pathogenesis. It is hypothesized that peripheral neurons may serve as an entry point for arboviral infection of the central nervous system. The objective of this study was to investigate whether and how macrophages and sensory neurons regulate each other during arboviral infections.
 We generated sensory neurons derived from human induced pluripotent stem cells, and macrophages derived from monocytes. We co-cultured them to establish a 2D in vitro system to investigate the response to Sindbis virus. Neurons were cultured with or without macrophages, and in presence of Sindbis-GFP virus to assess infectability and antiviral response of each cell type. We did not detect GFP expression or the viral genome in macrophages exposed to the virus, whereas neurons were significantly infected, regardless of the presence of macrophages. The expression of important elements of the antiviral response, such as interferons and interferon-stimulated genes, was modulated by the coculture conditions.
Investigation of gene expression profiles and phenotype of neurons and macrophages during an infection are in route using 2D and 3D culture approaches.