A Multimodal Imaging-Supported Down Syndrome Mouse Model of RSV Infection.

Individuals with Down syndrome (DS) are more prone to develop severe respiratory tract infections. Although a RSV infection has a high clinical impact and severe outcome in individuals with DS, no vaccine nor effective therapeutics are available. Any research into infection pathophysiology or prophylactic and therapeutic antiviral strategies in the specific context of DS would greatly benefit this patient population, but currently such relevant animal models are lacking. This study aimed to develop and characterize the first mouse model of RSV infection in a DS-specific context. Ts65Dn mice and wild type littermates were inoculated with a bioluminescence imaging-enabled recombinant human RSV to longitudinally track viral replication in host cells throughout infection progression. This resulted in an active infection in the upper airways and lungs with similar viral load in Ts65Dn mice and euploid mice. Flow cytometric analysis of leukocytes in lungs and spleen demonstrated immune alterations with lower CD8+ T cells and B-cells in Ts65Dn mice. Overall, our study presents a novel DS-specific mouse model of hRSV infection and shows that potential in using the Ts65Dn preclinical model to study immune-specific responses of RSV in the context of DS and supports the need for models representing the pathological development.

Multimodal in vivo Imaging of the Integrated Postnatal Development of Brain and Skull and Its Co-modulation With Neurodevelopment in a Down Syndrome Mouse Model.

The brain and skeletal systems are intimately integrated during development through common molecular pathways. This is evidenced by genetic disorders where brain and skull dysmorphologies are associated. However, the mechanisms underlying neural and skeletal interactions are poorly understood. Using the Ts65Dn mouse model of Down syndrome (DS) as a case example, we performed the first longitudinal assessment of brain, skull and neurobehavioral development to determine alterations in the coordinated morphogenesis of brain and skull. We optimized a multimodal protocol combining in vivo micro-computed tomography (µCT) and magnetic resonance imaging (µMRI) with morphometric analyses and neurodevelopmental tests to longitudinally monitor the different systems' development trajectories during the first postnatal weeks. We also explored the impact of a perinatal treatment with green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG), which can modulate cognition, brain and craniofacial development in DS. Our analyses quantified alterations associated with DS, with skull dysmorphologies appearing before brain anomalies, reduced integration and delayed acquisition of neurodevelopmental traits. Perinatal GTE-EGCG induced disparate effects and disrupted the magnitude of integration and covariation patterns between brain and skull. Our results exemplify how a longitudinal research approach evaluating the development of multiple systems can reveal the effect of morphological integration modulating the response of pathological phenotypes to treatment, furthering our understanding of complex genetic disorders.