Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model

Abstract

Down syndrome (DS), the genetic condition caused by trisomy 21, is characterized by variable cognitive impairment, immune dysregulation, dysmorphogenesis and increased prevalence of diverse co-occurring conditions. The mechanisms by which trisomy 21 causes these effects remain largely unknown. We demonstrate that triplication of the interferon receptor (IFNR) gene cluster on chromosome 21 is necessary for multiple phenotypes in a mouse model of DS. Whole-blood transcriptome analysis demonstrated that IFNR overexpression associates with chronic interferon hyperactivity and inflammation in people with DS. To define the contribution of this locus to DS phenotypes, we used genome editing to correct its copy number in a mouse model of DS, which normalized antiviral responses, prevented heart malformations, ameliorated developmental delays, improved cognition and attenuated craniofacial anomalies. Triplication of the Ifnr locus modulates hallmarks of DS in mice, suggesting that trisomy 21 elicits an interferonopathy potentially amenable to therapeutic intervention.

SARS-CoV-2 Infection Causes Heightened Disease Severity and Mortality in a Mouse Model of Down Syndrome

“…( Figure 5 D). This result is consistent with the triplication of Ifnar1 , Ifnar2 , and Ifngr2 in the Dp16;ACE2 mice [ 27 ] and indicates that mice with Down syndrome have a hyperactive IFN-I response during acute SARS-CoV-2 infection.…”

“…Because many social and behavioral factors, such as maintaining distance from others and wearing masks, can greatly alter SARS-CoV-2 transmission and the outcome of COVID-19, to better understand COVID-19 pathogenesis it is critical that experimental infection be conducted to ensure that all conditions are under control. We chose to model SARS-CoV-2 infection in the Dp(16)1Yey/+ mouse mutant line, which is triplicated for the entire human chromosome 21 syntenic region on mouse chromosome 16 and currently the most widely used mouse model of Down syndrome [ 14 , 23 , 24 , 25 , 26 , 27 ]. At the time the study commenced, it was reported in a preprint that a transgenic mouse model that expresses human ACE2 receptor (K18-hACE2) was susceptible to SARS-CoV-2 infection that resulted in severe lung inflammation and impaired function [ 28 , 29 ].…”

“…We addressed this important question by employing the mouse model of Down syndrome that has been widely used in the Down syndrome research community [ 14 , 23 , 24 , 25 , 26 , 27 ] for experimental infection with SARS-CoV-2, such that all experimental parameters and conditions are under control. Following intranasal inoculation with the same number of infectious viruses, the susceptibility of individual mice to SARS-CoV-2 was assessed by determining the virus loads in various organs.…”

“…Their results indicate that individuals with Down syndrome have fewer viral infections, but, when infected, they suffer from more severe disease [ 41 ], which is consistent with our observations in the mouse model of Down syndrome. A recent genetic study using the mouse model of Down syndrome also shows that in addition to exacerbation of the immune responses, triplication of the Ifnr locus contributes to other abnormalities typically seen in Down syndrome, such as heart defects, developmental delays, and craniofacial abnormalities [ 27 ]. Thus, the exacerbated IFN-I and IFN-II responses to SARS-CoV-2 infection observed in Dp16;ACE2 mice ( Figure 5 D) may contribute to the more severe COVID-19 in Down syndrome.…”

Increased lethality of respiratory infection by Streptococcus pneumoniae in the Dp16 mouse model of Down syndrome

“…Recently, the INCLUDE (INvestigation of Co‐occurring conditions across the Lifespan to Understand Down syndromE) program at NIH has ushered in a renaissance of new investigators, new ideas, and increased funding with the goal of helping persons with DS live longer and healthier lives. For example, trisomy 21 and the Dp16 mouse of DS have been associated with consistent activation of interferon responses 11,31 . Despite insights gained from studies on congenital abnormalities of airways and on immune cell defects, there are unfortunately few studies yet available that illuminate why people with DS are so susceptible to severe, lethal, and recurrent respiratory tract infection.…”