ABSTRACT
Coronavirus Disease 2019 (COVID-19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID-19 incidence and severity as a function of age. Our analysis leveraged age-specific COVID-19 mortality and laboratory testing from a large COVID-19 registry, along with epidemiological data of [~]3.4 million individuals, large-scale deep immune cell profiling data, and single-cell RNA-sequencing data from aged COVID-19 patients across diverse populations. To begin, we confirmed a significantly increased rate of severe outcomes in aged COVID-19 patients. Furthermore, we identified increased inflammatory markers (C-reactive protein, D-dimer, and neutrophil-lymphocyte ratio), viral entry factors in secretory cells, and TGF{beta}-mediated immune-epithelial cell interactions, as well as reduction in both naive CD8 T cells and expression of interferon antiviral defense genes (i.e., IFITM3 and TRIM22), along with strong TGF-beta mediated immune-epithelial cell interactions (i.e., secretory - T regulatory cells), in aged severe COVID-19 patients. Taken together, our findings point to immuno-inflammatory factors that could be targeted therapeutically to reduce morbidity and mortality in aged COVID-19 patients.
ABSTRACT
BackgroundDementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive interventions. MethodsIn this study, we conducted a network-based, multimodal genomics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9 based genetic assay results, and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimers disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. ResultsWe found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was significantly elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Notably, individuals with the AD risk allele APOE E4/E4 displayed reduced levels of antiviral defense genes compared to APOE E3/E3 individuals. ConclusionOur results suggest significant mechanistic overlap between AD and COVID-19, strongly centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions.
ABSTRACT
Objective:To evaluate the feasibility of a new ultrasonic parameter to assess right ventricular-pulmonary artery (RV-PA) coupling in patients with acute pulmonary embolism (APE).Methods:A retrospective analysis was performed in 140 patients with APE diagnosed by computed tomography pulmonary angiography (CTPA) in the Second Affiliated Hospital of Harbin Medical University from August 2017 to June 2020. According to the tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure (TAPSE/PASP) ratio cutoff value 0.40 mm/mmHg reported by the European Society of Cardiology in 2020, the patients were divided into the coupling group ( n=99) and the uncoupling group ( n=41). The conventional ultrasonic parameters of the 2 groups were measured, and then several ultrasonic parameter ratios were obtained. The new ultrasonic parameter, which can replace the TAPSE/PASP ratio, was screened out by Spearman correlation analysis, and ROC curve was plotted to calculate the diagnostic efficacy of this parameter. Results:①Compared with the coupling group, patients in the uncoupling group were older and more likely to be accompanied by dyspnea and venous thrombosis in the lower extremities (all P<0.05), but there was no significant difference in other general data(all P>0.05); ②Compared with the coupling group, tricuspid regurgitation velocity (TRV), tricuspid regurgitation pressure gradient(TRPG), PASP, right ventricle end-diastolic transverse diameter(RVTD), inferior vena cava(IVC) diameter and the ratio of early diastolic tricuspid inflow to tricuspid lateral annular velocity(E/e′), in the uncoupling group increased significantly (all P<0.05), and TAPSE, peak systolic velocity of tricuspid annulus(s′), TAPSE/PASP ratio, TAPSE/TRPG ratio, TAPSE/RVTD ratio and s′/TRPG ratio decreased significantly (all P<0.05); ③The TAPSE/TRPG ratio was highly correlated with TAPSE/PASP ratio ( rs=0.970, P<0.001); The TAPSE/TRPG ratio was still highly correlated with TAPSE/PASP ratio in the uncoupling and coupling groups ( rs=0.966, 0.922; all P<0.001). ④ROC analysis showed that the area under curve for TAPSE/TRPG in diagnosing RV-PA coupling was 0.992. At the cutoff of TAPSE/TRPG <0.625 mm/mmHg for indicating RV-PA coupling, the sensitivity and specificity were 97.6% and 92.9%, respectively. Conclusions:TAPSE/TRPG ratio can be used as a new ultrasonic parameter to reflect RV-PA coupling, which is helpful for clinical identification of APE patients with high risk and poor prognosis.
ABSTRACT
The recent COVID-19 pandemic has sparked a global public health crisis. Vital to the development of informed treatments for this disease is a comprehensive understanding of the molecular interactions involved in disease pathology. One lens through which we can better understand this pathology is through the network of protein-protein interactions between its viral agent, SARS-CoV-2, and its human host. For instance, increased infectivity of SARS-CoV-2 compared to SARS-CoV can be explained by rapid evolution along the interface between the Spike protein and its human receptor (ACE2) leading to increased binding affinity. Sequence divergences that modulate other protein-protein interactions may further explain differences in transmission and virulence in this novel coronavirus. To facilitate these comparisons, we combined homology-based structural modeling with the ECLAIR pipeline for interface prediction at residue resolution, and molecular docking with PyRosetta. This enabled us to compile a novel 3D structural interactome meta-analysis for the published interactome network between SARS-CoV-2 and human. This resource includes docked structures for all interactions with protein structures, enrichment analysis of variation along interfaces, predicted {Delta}{Delta}G between SARS-CoV and SARS-CoV-2 variants for each interaction, predicted impact of natural human population variation on binding affinity, and a further prioritized set of drug repurposing candidates predicted to overlap with protein interfaces{dagger}. All predictions are available online{dagger} for easy access and are continually updated when new interactions are published. {dagger}Some sections of this pre-print have been redacted to comply with current bioRxiv policy restricting the dissemination of purely in silico results predicting potential therapies for SARS-CoV-2 that have not undergone thorough peer-review. The results section titled "Prioritization of Candidate Inhibitors of SARS-CoV-2-Human Interactions Through Binding Site Comparison," Figure 4, Supplemental Table 9, and all links to our web resource have been removed. Blank headers left in place to preserve structure and item numbering. Our full manuscript will be published in an appropriate journal following peer-review.
