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Single Nuclei RNA Sequencing Analysis of Cardiac Microthrombi in Fatal Covid-19

ABSTRACT: Cardiac microthrombi have been variably identified at autopsy of Covid-19 decedents. Little is known about the morphologic and molecular changes associated with cardiac microthrombi and whether predictive biomarkers exist. We sought to determine the prevalence, pathogenesis, and biomarker risk factors of Covid-19-associated cardiac microthrombi. In addition to histology and immunohistochemical analyses, we investigated right verticles from 8 Covid-19 decedents via single nuclei RNA sequencing for cell-type specific transcriptional differences between hearts with and without microthrombi, as well as between Covid-19 decedents and publicly available non-Covid-19 donor controls.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185457 | GEO | 2021/12/28

REPOSITORIES: GEO

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Project description:Since the beginning of the SARS-CoV-2 pandemic, COVID-19 has appeared as a unique disease with unconventional tissue and systemic immune features. While COVID-19 severe forms share clinical and laboratory aspects with various pathologies such as hemophagocytic lymphohistiocytosis, sepsis or cytokine release syndrome, their exact nature remains unknown. This is severely impeding the ability to treat patients facing severe stages of the disease. To this aim, we performed an in-depth, single-cell RNA-seq analysis of more than 150.000 immune cells isolated from matched blood samples and broncho-alveolar lavage fluids of COVID-19 patients and healthy controls, and integrated it with clinical, immunological and functional ex vivo data. We unveiled an immune signature of disease severity that correlated with the accumulation of naïve lymphoid cells in the lung and an expansion and activation of myeloid cells in the periphery. Moreover, we demonstrated that myeloid-driven immune suppression is a hallmark of COVID-19 evolution and arginase 1 expression is significantly associated with monocyte immune regulatory features. Noteworthy, we found monocyte and neutro-phil immune suppression loss associated with fatal clinical outcome in severe patients. Additionally, our analysis discovered that the strongest association of the patients clinical outcome and immune phenotype is the lung T cell response. We found that patients with a robust CXCR6+ effector memory T cell response have better outcomes. This result is line with the rs11385942 COVID-19 risk allele, which is in proximity to the CXCR6 gene and suggest effector memory T cell are a primary feature in COVID-19 patients. By systemically quantifying the viral landscape in the lung of severe patients, we indeed identified Herpes-Simplex-Virus 1 (HSV-1) as a potential opportunistic virus in COVID-19 patients. Lastly, we observed an unexpectedly high SARS-CoV-2 viral load in an immuno-compromised patient, allowing us to study the SARS-CoV-2 in-vivo life cycle. The development of my-eloid dysfunctions and the impairment of lymphoid arm establish a condition of immune paralysis that supports secondary bacteria and virus infection and can progress to “immune silence” in patients facing death.

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Single Nuclei RNA Sequencing Analysis of Cardiac Microthrombi in Fatal Covid-19

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