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Using Transcriptomics to Investigate Cardiovascular Risk Factors for COVID-19
June 24, 2020
Of the few publications with published gene expression data from Covid-19 patients, a recent manuscript in ‘Emerging Microbes and Infections’ investigated the transcriptomic host response to infection of SARS-CoV-2. In our previous posts, we shared the results of using this publication’s transcriptional data with PercayAI’s CompBio™ tool for both the bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cells (PBMC) samples in parts one and two, respectively.
Beyond simply understanding the biological processes and pathways taking place in PBMC and BALF samples during COVID-19, we wanted to use these data to investigate some of the cardiovascular risk factors and sequelae associated with poor COVID-19 outcomes.
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First, given that cardiovascular disease and aging are known risk factors, we used a publicly available transcriptomics study of aging cardiac mesenchymal stromal cells to perform a concept-level comparison between aging cardiac cells and PBMCs from COVID-19 patients.
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Next, to better understand how COVID-19 leads to various thrombotic events throughout the body, we performed a concept-level comparison of PBMCs from COVID-19 patients with a knowledge map generated from the query term “thrombotic microangiopathy."
At PercayAI, we want to share transparent analyses with the scientific community in order to help uncover novel hypotheses to target Covid-19. We are therefore using our AI tools to help colleagues worldwide gain a better collective understanding of the virus and potential treatments.
We ask other researchers to join us. If you have COVID-19 data you'd like us to analyze using CompBio, free of charge, reach out here to get in touch with our team.
COVID-19 and Cardiovascular Pathology
Here, we used the upregulated transcriptomic profile of PBMC samples from COVID-19 patients and our concept-level comparison feature in our tool to work to answer two questions:
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Why are older patients at higher risk for worse outcomes, especially those with cardiovascular comorbidities?
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What mechanisms may be leading to thrombotic microangiopathy in COVID-19 patients?
Upregulated Host Response to COVID-19
First, we created a map of the biology upregulated within PBMC samples from COVID-19 patients.
Map of COVID patient PBMC
General Overview:
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In purple (right), a number of cellular metabolism processes are enhanced, potentially suggesting high energy consumption within the blood cells.
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In teal (bottom), there is an immune cluster that includes a specific macrophage signature, immunoglobulins and complement signaling.
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In blue (center, right) are cell fate related themes, which focus on replication and cell cycle regulation.
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In green (middle, left), there are a few processes that are associated with cell motility and ECM reorganization, including VEGF-A signaling.
Key Takeaways:
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Together, the cellular metabolism and cell fate themes may indicate that the cells are very active and are proliferating. This might indicate dysregulation of these processes due to the viral infection, or a compensatory response to address the virus’s determetrial effects.
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Interestingly, we found that macrophages seem to be the immune cell type that is upregulated in response to the viral infection. We might expect to see a wider variety of immune cells activated, though this does not seem to be the case.
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Recently, there has been interest in the effect of complement signaling within COVID-19 disease state. As has been found in many other studies, we found that complement signaling is upregulated within circulation of these patients.
Interrogating COVID-19 Risk Factor: Aging Cardiac Cells
Next, to interrogate potential mechanisms by which elderly individuals and individuals with cardiovascular disease are predisposed to more severe COVID-19 pathology, we performed a concept-level comparison of the knowledge map of PBMCs from COVID-19 patients with the knowledge map from a transcriptomics study of cardiac mesenchymal stromal cells from aging mice. The map shown here displays only the biological processes and pathways shared by COVID-19 patient blood samples and cardiac cells from an aging mouse model. The ratios in red display the number of concepts within that theme (in-common/total).
Map from COVID blood samples showing only biological concepts that also occur within aging mouse cardiac cells.
General Overview:
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In purple (right), only a few of the cellular metabolism processes remain in the comparison.
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In teal (bottom), much of the immune cluster remains including the macrophage signature, immunoglobulins and complement signaling.
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No cell fate related themes remain.
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In green (middle, right), only VEGF-A signaling remains.
Key Takeaways:
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Together, the reduced presence of the cellular metabolic processes and the absence of cell fate themes may indicate that the cells have very different levels of cell reproduction and energy consumption. This might be expected when comparing an activated state of disease to an aging phenotype.
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We found that the macrophage and phagocyte signature is shared by the aging cardiac cells as well.
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Interestingly, complement signaling is common across aging cardiac cells and COVID-19 disease state with almost all the concepts remaining conserved. This indicates that complement signaling is highly associated between these conditions.
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We find it very interesting that complement signaling and the macrophage/phagocyte signature are both conserved between aging cardiac cells and the COVID-19 disease state. The overactivation of complement signaling in both cases might indicate that aging cardiac cells (or more broadly, an aging heart), are predisposed to more severe COVID-19 disease progression.
Interrogating COVID-19 Complication: Thrombotic Microangiopathy
Next, we investigated a possible consequence of overactivation of complement signaling. Thrombotic Microangiopathy can occur through many different biological mechanisms, including overactivation of complement signaling. Thrombotic microangiopathy is clotting with small vessels. This can lead to many complications including organ damage, particularly in the kidneys. Thrombotic microangiopathy is hypothesized to play a role in several of the manifestations of COVID-19, as seen in articles such as here or here.
Map from COVID blood samples showing only biological concepts also associated with thrombotic microangiopathy.
General Overview:
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In purple (middle), a few cellular metabolism processes are in common.
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In teal (bottom), remaining in the immune cluster is the immunoglobins and complement signaling signatures.
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In green (middle, left), a few processes that are associated with ECM reorganization and VEGF-A signaling remain.
Key Takeaways:
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Through comparison of clinical blood samples from COVID-19 patients and two associated biological complications, aging cardiovascular problems and thrombosis, we show that our tool identifies and explores commonalities. Exploring these commonalities may help us find links underlying this disease’s severity and uncover targets for treatment.
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First, we find that complement signaling is activated in COVID-19 and in aging cardiac cells, showing a possible mechanism for increased susceptibility. Furthermore, complement signaling is tied to thrombotic microangiopathy. Inhibition of complement signaling may be an important target in the most severe cases.
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Second, we find that VEGF signaling seems to be linked in all these conditions as well. This pathway is not yet well studied in COVID-19 research, though it has been found to be related to thrombotic microangiopathy within the kidney.
We believe there’s value in collaboration, and we’d like to know what you think. Please leave us a comment below with your thoughts, hypothesis or additional questions, and we may address it in future analyses.
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