Pulmonary mesenchymal stem cells are engaged in distinct steps of host response to respiratory syncytial virus infection

Brügger, Melanie; Démoulins, Thomas; Barut, G. Tuba; Zumkehr, Beatrice; Oliveira Esteves, Blandina I.; Mehinagic, Kemal; Haas, Quentin; Schögler, Aline; Rameix-Welti, Marie-Anne; Eléouët, Jean-François; Moehrlen, Ueli; Marti, Thomas M.; Schmid, Ralph A.; Summerfield, Artur; Posthaus, Horst; Ruggli, Nicolas; Hall, Sean R. R.; Alves, Marco P.

Lung-resident (LR) mesenchymal stem and stromal cells (MSCs) are key elements of the alveolar niche and fundamental regulators of homeostasis and regeneration. We interrogated their function during virus-induced lung injury using the highly prevalent respiratory syncytial virus (RSV) which causes severe outcomes in infants. We applied complementary approaches with primary pediatric LR-MSCs and a state-of-the-art model of human RSV infection in lamb. Remarkably, RSV-infection of pediatric LR-MSCs led to a robust activation, characterized by a strong antiviral and pro-inflammatory phenotype combined with mediators related to T cell function. In line with this, following in vivo infection, RSV invades and activates LR-MSCs, resulting in the expansion of the pulmonary MSC pool. Moreover, the global transcriptional response of LR-MSCs appears to follow RSV disease, switching from an early antiviral signature to repair mechanisms including differentiation, tissue remodeling, and angiogenesis. These findings demonstrate the involvement of LR-MSCs during virus-mediated acute lung injury and may have therapeutic implications.