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Cardiovascular-related proteomic changes in ECFCs exposed to the serum of COVID-19 patients

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection not only exerts a deep impact over the respiratory system, but it also affects the cardiovascular system, causing vascular damage and thromboembolic events in critical patients. The endothelial dysfunction taking place in response to COVID-19 represents one of the first steps in this cascade of events that might leads to long-term sequelae over the vascular function. However, despite the enormous efforts in the last two years, the molecular mechanisms involved in such processes remains poorly understood. Using a label free-quantitative proteomics approach, we profiled the proteome of endothelial colony forming cells (ECFCs), after its incubation with the serum from individuals infected with COVID-19, whether asymptomatic or critical patients. Specifically, ECFCs were incubated ex-vivo with the serum of either SARS-CoV-2 negative donors (PCR-/IgG-), SARS-CoV-2 positive asymptomatic donors, at different infective stages: PCR+/ IgG- and PCR-/IgG+, or hospitalized critical COVID-19 patients, followed by mass spectrometry analysis. Remarkably, in response to all infected serums, the differentially expressed protein were found to be correlated with alterations in viral infection, RNA metabolism or autophagy, among others. Moreover, the serum of critical patients promoted the highest number of protein alterations, many of which associated with cardiovascular related pathologies. Finally, machine learning algorithms confirmed the discriminating potential of some proteins differentially expressed between conditions.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Santosh Bhosale

LAB HEAD: Martin Røssel Larsen

PROVIDER: PXD034620 | Pride | 2023-03-20

REPOSITORIES: Pride

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Project description:Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has provoked, up to date, more than 5 million deaths worldwide. While asymptomatic individuals are responsible of many potential transmissions, the difficulty to identify and isolate them at the high peak of infection constitutes still a real challenge in the actual pandemic. Moreover, apart from the effect over the respiratory system, SARS-CoV-2 provokes severe vascular damage and thromboembolic events in critical COVID-19 patients, deriving in many related deaths and long-hauler symptoms. Understanding how these processes are triggered in response to the virus as well as the potential sequelae at the long term, even in asymptomatic donors, becomes essential. Methods: We have evaluated, by application of a proteomics-based quantitative approach, the effect of serum of COVID-19 asymptomatic individuals over circulating angiogenic cells (CACs). Thus, healthy CACs were incubated ex-vivo with the serum of either COVID-19 negative (PCR-/IgG-, n:8) or COVID-19 positive asymptomatic donors, at different infective stages: PCR+/ IgG- (n:8) and PCR-/IgG+ (n:8). Also, a label free quantitative approach was applied to identify and quantify protein differences between these serums. Results: Our results confirmed that SARS-CoV-2 promotes changes at the protein level in the serum of infected asymptomatic individuals, mainly correlated with altered coagulation and inflammatory processes (Fibrinogen, Von Willebrand Factor, Thrombospondin-1). At the cellular level, proteins like ICAM-1, TLR2 or Ezrin/Radixin were only up-regulated in CACs treated with the serum of asymptomatic patients at the highest peak of infection (PCR+/IgG-), but not with the serum of PCR-/IgG+ individuals. Many of these proteins correlate with the initial response of the endothelium against the virus. Conclusions: The incubation ex vivo of CACs with the serum of asymptomatic COVID-19 donors at different stages of infection promoted protein changes representative of the endothelial dysfunction and inflammatory response that occur after viral infection, together with activation of the coagulation process. The current approach constitutes an optimal model to study the response of vascular cells to SARS-CoV-2 infection, as well as an alternative to test potential inhibitors targeting either the virus entry pathway or molecules involved in the immune responses following SARS-CoV-2 infection.

Project description:In the last two years, the coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a scientific and social challenge worldwide. Vaccines have been the most effective intervention for reducing virus transmission and disease severity. However, virus genetic variants are still circulating among vaccinated individuals with different symptomatology disease cases. Understanding the protective or disease associated mechanisms in vaccinated individuals is relevant to advance in vaccine development and implementation. To address this objective, serum protein profiles were characterized by quantitative proteomics and data analysis algorithms in four cohorts of vaccinated individuals uninfected and SARS-CoV-2 infected with asymptomatic, nonsevere and severe disease symptomatology. The results showed that immunoglobulins were the most overrepresented proteins in infected cohorts when compared to PCR-negative individuals. The immunoglobulin profile varied between different infected cohorts and correlated with protective or disease associated capacity. Overrepresented immunoglobulins in PCR-positive individuals correlated with protective response against SARS-CoV-2, other viruses, and thrombosis in asymptomatic cases. In nonsevere cases, correlates of protection against SARS-CoV-2 and HBV together with risk of myasthenia gravis and allergy and autoantibodies were observed. Patients with severe symptoms presented risk for allergy, chronic idiopathic thrombocytopenic purpura, and autoantibodies. The analysis of underrepresented immunoglobulins in PCR-positive compared to PCR-negative individuals identified vaccine-induced protective epitopes in various coronavirus proteins including the Spike receptor-binding domain RBD. Non-immunoglobulin proteins were associated with COVID-19 symptoms and biological processes. These results evidence host-associated differences in response to vaccination and the possibility of improving vaccine efficacy against SARS-CoV-2.

			Action	DRS
	ECFCs_Critical.7z	Other
	ECFCs_DirectDIA_Spectronaut_Report.txt	Txt
	ECFCs_IgG-Positive.7z	Other
	ECFCs_Neg.7z	Other
	ECFCs_PCR-Positive.7z	Other

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Cardiovascular-related proteomic changes in ECFCs exposed to the serum of COVID-19 patients

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