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Aicardi Goutières Syndrome (AGS) is an autoinflammatory disorder resulting in sustained interferon activation through defects in nucleic acid modification and sensing pathways. Thus, mRNA-based vaccination used against SARS-CoV-2, raise disease-specific safety concerns. To assess interferon signaling, we tested mRNA SARS-CoV-2 vaccines in AGS whole blood samples. Interferon activation is measured through quantitation of interferon signaling gene (ISG) expression and is increased in AGS patients. There was no increase in ISG scores from baseline following treatment with the nucleoside modified mRNA formulation compared to an increase with unmodified. A patient-family survey reported that the vaccines were well tolerated. These findings suggest that COVID vaccination using nucleoside-modified forms of mRNA vaccines are unlikely to directly stimulate ISG expression in response to mRNA internalization in AGS tissues. With continued community spread, we recommend vaccination using nucleoside-modified mRNA vaccines in this rare disease group in individuals for whom vaccines were previously well tolerated.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses threats to individuals with rare disease, in part because so little is known about the impact of COVID-19 infection and vaccination safety in rare disease populations. Of particular concern, given the overlap in disease manifestations and interferon dysregulation, are a group of heritable autoinflammatory conditions called type I interferonopathies. The most common of these, Aicardi Goutières Syndrome (AGS), is caused by altered nucleic acid metabolism and sensing, resulting in additional concerns surrounding the use of mRNA vaccination approaches. To determine whether mRNA vaccines induce an interferon response in AGS, we applied mRNA SARS-CoV-2 vaccines to whole blood samples and assessed internalization and interferon signaling gene expression responses to the mRNA. In all cases (11 AGS and 11 control samples), interferon signatures did not significantly increase from baseline, regardless of baricitinib treatment status in the AGS subjects, and were even decreased, when using codon optimized SARS-CoV-2 di-proline modified spike sequence (S2P). Internalization of S2P in human dendritic cells was verified by Western Blot, and in control and AGS blood cells was verified by Luciferase activity. Although numbers of tested samples in this rare disease are small, based on these findings, we suggest that COVID vaccination is unlikely to directly stimulate the interferon signaling gene expression in AGS patients via response to mRNA internalization. The in vitro nature of this study cannot exclude an exaggerated interferon response to spike protein production at a systemic level in individuals with a primary heritable interferonopathy. In the context of continued SARS-CoV-2 spread in the community, we do not recommend withholding vaccination in this rare disease group. However, we recommend that vaccinations for AGS patients are provided in a controlled setting with appropriate observation and used with caution in individuals with prior vaccine associated adverse events.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias and sudden cardiac death. We previously demonstrated that cardiac-specific overexpression of human mutant desmoplakin (DSPR2834H) leads to ARVC in mice at 6 months of age. However, the potential role and mechanism(s) of DSP in preclinical ARVC under cardiac stress remains unclear. Objectives: This study is aimed to elucidate the impact of DSP in the development of ARVC under adrenergic stimulation. Methods: Three-month-old non-transgenic (NTg), wild-type DSP (Tg-DSPWT) and Tg-DSPR2834H mice without obvious signs of ARVC, including right and left ventricular dysfunction, arrhythmias, were infused with either vehicle or isoproterenol (30mg/kg/d) for 2 weeks using mini-osmotic pumps. During isoproterenol infusion, electrocardiography (ECG) was monitored daily on conscious mice. Echocardiography and cardiac MRI were performed before and after 2-week of isoproterenol infusion. Myocardial tissues from both RV and LV were subjected to cellular, biochemical and histopathological analysis. Results: Isoproterenol resulted in cardiac hypertrophy to a similar degree amongst all genotypes; however, mortality occurred only in Tg-DSPR2834H mice. Vehicle-treated mice from all genotypes showed largely normal ECGs, whereas isoproterenol led to various types of arrhythmia in Tg-DSPR2834H mice including ventricular tachycardia and QT prolongation. Echocardiography analysis revealed LV dysfunction (decreased factional shortening) in isoproterenol-treated Tg-DSPR2834H mice compared to other treatment groups. Interstitial fibrosis and lipid infiltration was prominent in the Tg-DSPR2834H myocardium. MRI analysis is being performed to understand the RV and LV geometry and function. Conclusion: Our preliminary data confirms the essential role of desmoplakin in response to adrenergic stimulation. Studies investigating the electrophysiological, geometrical and cellular mechanisms of the pro-arrhythmic nature of DSPR2834H dysfunction are ongoing which may ultimately provide critical experimental data on prevention of asymptomatic preclinical ARVC in humans.

Despite its importance, relatively little is known about the relationship between the structure, function, and evolution of proteins, particularly in land plant species. We have developed a database with predicted protein domains for five plant proteomes (http://pfp.bio.nyu.edu) and used both protein structural fold recognition and de novo Rosetta-based protein structure prediction to predict protein structure for Arabidopsis and rice proteins. Based on sequence similarity, we have identified ~15,000 orthologous/paralogous protein family clusters among these species and used codon-based models to predict positive selection in protein evolution within 175 of these sequence clusters. Our results show that codons that display positive selection appear to be less frequent in helical and strand regions and are overrepresented in amino acid residues that are associated with a change in protein secondary structure. Like in other organisms, disordered protein regions also appear to have more selected sites. Structural information provides new functional insights into specific plant proteins and allows us to map positively selected amino acid sites onto protein structures and view these sites in a structural and functional context.

The incompleteness of proteome structure and function annotation is a critical problem for biologists and, in particular, severely limits interpretation of high-throughput and next-generation experiments. We have developed a proteome annotation pipeline based on structure prediction, where function and structure annotations are generated using an integration of sequence comparison, fold recognition, and grid-computing-enabled de novo structure prediction. We predict protein domain boundaries and three-dimensional (3D) structures for protein domains from 94 genomes (including human, Arabidopsis, rice, mouse, fly, yeast, Escherichia coli, and worm). De novo structure predictions were distributed on a grid of more than 1.5 million CPUs worldwide (World Community Grid). We generated significant numbers of new confident fold annotations (9% of domains that are otherwise unannotated in these genomes). We demonstrate that predicted structures can be combined with annotations from the Gene Ontology database to predict new and more specific molecular functions.