Dataset Information

Clinical features and Multiomics Profiles Indicate Coagulation and Platelet Dysfunction as Key Pathological Pathways in COVID-19 Viral Sepsis

ABSTRACT: Background: The role of viral infections as a mediator of systemic immune dysfunction leading to sepsis has received limited attention compared to the bacterial pathogens. The COVID-19 pandemic and the increased cases of sepsis in the absence of known bacterial pathogens have highlighted the clinical relevance of viruses as causative agents of sepsis. In this study, we investigated clinical, laboratory, proteomic, and metabolic characteristics to shed light on the molecular mechanisms underlying the pathological conditions of viral sepsis in COVID-19. Methods: We retrospectively analyzed data from 231 hospitalized patients with confirmed COVID-19 admitted to three hospitals in China. The presence of viral sepsis was diagnosed with SOFA score 2 in the absence of bacterial infection. Demographics, clinical, and laboratory parameters, as well as clinical outcomes, were obtained from electronic chart reviews. Plasma samples were obtained from a subset of these patients (23 patients in the Viral Non-Sepsis [VNS] group and 14 patients in the Viral Sepsis [VS] group) to analyze proteomic and metabolic profiles. Findings: The viral sepsis group exhibited severe disease, as indicated by elevated markers of both pulmonary (ARDS) and systemic disease (liver, kidney, and cardiac injury). Consistent with known immune paralysis observed in sepsis, subjects with viral sepsis were more susceptible to secondary infections by bacterial and fungal pathogens. Overall, viral sepsis led to an increased length of ICU stay, required invasive mechanical ventilation and a significant increase in mortality compared to the non-viral sepsis group. At the molecular levels, we identified unique metabolic and proteomic signatures that suggest a substantial contribution of the coagulation and platelet dysfunction pathways to systemic pathologies. Interpretation: Viral sepsis presents an underrecognized threat contributing to high mortality. Specific metabolic and proteomic changes demonstrated coagulation and platelet dysfunction as key pathological pathway in viral sepsis.

ORGANISM(S): Homo Sapiens

SUBMITTER: De Chang

PROVIDER: PXD050303 | iProX | Sun Mar 03 00:00:00 GMT 2024

REPOSITORIES: iProX

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Clinical features and multiomics profiles indicate coagulation and platelet dysfunction in COVID-19 viral sepsis.

Xiao Zhiqing Z Lin Minggui M Song Ning N Wu Xue X Hou Jingyu J Wang Lili L Tian XinLun X An Chunge C Dela Cruz Charles S CS Sharma Lokesh L Chang De

iScience 20240525 6

Increased cases of sepsis during COVID-19 in the absence of known bacterial pathogens highlighted role of viruses as causative agents of sepsis. In this study, we investigated clinical, laboratory, proteomic, and metabolomic characteristics of viral sepsis patients (<i>n</i> = 45) and compared them to non-sepsis patients with COVID-19 (<i>n</i> = 186) to identify molecular mechanisms underlying the pathology of viral sepsis in COVID-19. We identified unique metabolomic and proteomic signatures t ...[more]

PMID: 38974472

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Project description:SARS-CoV-2 primarily affects the respiratory system but extra-pulmonary manifestations in individuals with COVID-19 are commonly seen. All major organ systems have been reported to be affected by SARS-CoV-2 and complications arising from ensuing organ dysfunction significantly increase the mortality rate of COVID-19. Yet, despite the clinical importance of systemic involvement of SARS-CoV-2, little is known about the pathogenesis of extra-pulmonary complications of COVID-19. Here, we create a murine model of SARS-CoV-2 induced severe systemic toxicity and multi- organ involvement by expressing the human ACE2 transgene in multiple tissues using an adeno associated virus (serotype 9) followed by administration of the SARS-CoV-2 virus intra-peritoneally. The animals develop a profound phenotype within 7 days of SARS-CoV-2 infection with severe weight loss, morbidity and failure to thrive, that necessitated euthanasia. We demonstrate that following a robust anti-viral immune response, there is metabolic suppression of oxidative phosphorylation and the tri- carboxylic acid (TCA) cycle in multiple organs with neutrophilia, lymphopenia and splenic atrophy mirroring human COVID-19 phenotypes with adverse prognosis. Animals had a significantly lower heart rate and electron microscopy demonstrated myofibrillar disarray and myocardial edema, a common pathogenic cardiac phenotype in human COVID-19. An organ wide metabolic reprogramming consistent with depression of oxidative phosphorylation led to utilization of peripheral fat stores and gross accumulation of fat in the heart and other vital organs. We perform metabolomic profiling of peripheral blood and identify a panel of TCA cycle metabolites that serve as biomarkers of depressed oxidative phosphorylation, several of these markers been noted in human clinical studies to be associated with adverse prognosis. Finally, we observed that SARS-CoV-2 induces epigenetic changes with a significant number of differentially methylated sites in vital organs, across the whole host cell genome, that affects expression of immune response genes and could in part contribute to dysregulated gene expression in affected tissues. Our model suggests that SARS-CoV- 2 induced metabolic reprogramming and epigenetic changes in internal organs could contribute to systemic toxicity and lethality in COVID-19.

Dataset Information

Clinical features and Multiomics Profiles Indicate Coagulation and Platelet Dysfunction as Key Pathological Pathways in COVID-19 Viral Sepsis

Publications

Clinical features and multiomics profiles indicate coagulation and platelet dysfunction in COVID-19 viral sepsis.

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