Predicting the Outcome of COVID-19: GigaScience at the Human Cell Atlas COVID-19 Virtual Symposium

cell atlas symposium

The Human Cell Atlas is a consortium that aims to “create comprehensive reference maps of all human cells—the fundamental units of life—as a basis for both understanding human health and diagnosing, monitoring, and treating disease.” I first met with consortium members of the Human Cell Atlas at the Human BioMolecular Atlas Program Common Coordinates Framework Workshop based at the National Institutes of Health, Bethesda, USA in December 2017. Since then the world has changed, and the COVID-19 pandemic is very much at the forefront of our minds. Towards this end, the Human Cell Atlas organised a COVID-19 Virtual Symposium on the 1st and 9th October 2020 to highlight important research findings in host responses, pathophysiology, and immunology. I attended this virtual conference and report below on some of the key investigations that are helping us to understand the mechanisms of COVID-19 disease.

When COVID-19 Kills – The Mechanisms of a Lethal Disease
Keynote speaker Carlos Cordon-Cardo (Icahn School of Medicine at Mount Sinai, New York), in his talk entitled “Contribution of Pathology in COVID-19”, detailed the testing strategy employed in Mount Sinai Hospital, New York City and highlighted that viral load of the SARS-CoV-2 pathogen at diagnosis – the viral pathogen responsible for COVID-19 – is a critical determinant of survival. As Carlos explains, “a high viral load at diagnosis is significantly associated with death in COVID-19 patients.” Carlos further highlighted autopsy findings of lethal cases of COVID-19, such as hyaline membrane formation in damaged lung tissue, whereby necrotic tissue impede gas exchange in the lower airways, and macrophage activation which induces production of proinflammatory cytokines, chemokines, and prostaglandins in the lower airways that recruit immune cells into the lung. The immune cell infiltrate and the accompanying pulmonary oedema (excessive fluid in the lung) greatly thicken the respiratory membrane and adversely affect breathing. In addition, Carlos highlighted similarities between lethal COVID-19 and Macrophage Activation Syndrome (MAS), whereby the macrophage – a key immune cell in the orchestration of an inflammatory response – is unable to switch off its proinflammatory program. The body’s inability to shutdown the overactive response of the macrophage population in the lungs may lead to an excessive systemic immune response that can be life-threatening to the COVID-19 patient.

Movie of Carlos Cordon-Cardo’s talk.

COVID-19 is a Systemic Disease requiring Diagnostic Staging
Carlos Cordon-Cardo additionally highlighted the need to provide a more detailed staging system for COVID-19, similar to the clinical staging criteria that are used to diagnose metastatic disease. Indeed, from a clinical management perspective there are similarities with the staging of COVID-19 and the pathophysiology of cancer. With COVID-19, we see a primary SARS-CoV-2 infection of the airways, a subsequent ‘intravasation’ into the bloodstream, and a later ‘extravasation’ into a distant tissue such as endothelium of the brain or the kidney. Carlos emphasises the need for a staging of this new COVID-19 disease – in terms of viral entry and replication, viral dissemination, multisystem inflammation, and endothelial damage – as a means of understanding some of the late-stage features that he observes in lethal COVID-19, such as multiple micro-infarcts and thromboembolisms in the small vessels of the brain. As Carlos explains, “These studies reveal that COVID-19, conceptualized as a primarily respiratory viral illness, also causes endothelial dysfunction and a hypercoagualable state…the coagulopathy and hypoxia in severely ill patients generate a multi-organ failure leading in certain instances to death”.

Can ACE Inhibitors Adversely Affect COVID-19 Outcome?
I was further intrigued by the presentation by Anna Greka of the Broad Institute on the tissue distribution of the ACE2 cell surface receptor. The SARS-CoV-2 virus primarily infects human cells by binding to the ACE2 cell surface receptor (see recent GigaBlog). This receptor is enriched in the upper airways, but as Anna explains “ACE2 is highly expressed in the tubular compartments of the kidney.” So what does the ACE2 receptor do? ACE2, or Angiotensin-converting enzyme 2, lowers blood pressure by converting the vasoconstrictor peptide Angiotensin II to the vasodilatory peptide Angiotensin I, and thus counteracts the function of Angiotensin-converting enzyme (ACE) which instead promotes formation of the vasoconstrictor Angiotensin II. ACE inhibitors are widely used to treat high blood pressure, and Anna provided tantalising preliminary data that highlighted higher expression of ACE2 in kidney cells of patients treated with ACE inhibitors. As Anna explains, “ACE2 expression is modulated by blood pressure medications that target ACE.” So what does this mean for SARS-CoV-2 infected individuals? Are they at higher risk of acute kidney injury if they are receiving medication for high blood pressure? In addition, for uninfected individuals treated with ACE inhibitors, are they at higher risk of SARS-CoV-2 infection by virtue of overexpressing the ACE2 receptor that the SARS-CoV-2 coronavirus uses as its point of entry?  Furthermore, is the potentially dangerous complication of SARS-CoV-2 viral transduction into the nephron – the functional unit of the kidney – dependent on blood pressure medications that are more frequently administered to older patients? Anna was quick to point out that these are preliminary data and that the findings are “not statistically powerful”, but that there is a salient need in the Human Cell Atlas framework for clinical metadata relating to patient medications to enable a more detailed analysis.

Movie of Anna Greka’s talk.

Understanding Variability of COVID-19 Outcome – Perspectives on the Immune Response
A lethal outcome is the worst-case scenario, but only a small proportion of SARS-CoV-2 infected individuals develop clinical complications such as pulmonary embolism and stroke. So how is COVID-19 outcome so variable? Ben tenOever (Icahn School of Medicine at Mount Sinai, New York) highlights the role of the Type I Interferon (IFN) response – a potent antiviral response that will often induce a high fever – in severity of outcome. As Ben explains, the cellular response to virus infection utilises a “call to arms” that uses Type I IFN immunoregulatory cytokine signalling proteins as critical intermediates, and a distinct “call for reinforcements” which utilises the NF-kappaB chemokine response pathway. Ben further explains that SARS-CoV-2 can, to a degree, inhibit the Type I IFN response and can therefore dampen the effect of this potent antiviral signalling pathway, which is known to interfere with viral replication by upregulating key antiviral genes such as 2’–5′-oligoadenylate synthetase (OAS). However, the chemokine-responsive infiltration of leukocytes can continue in SARS-CoV-2-infected tissue, and this may indeed represent the COVID-19 ‘Achilles heel’ of our immune system. Indeed, by disabling the “call to arms” but not the “call for reinforcements”, one can envisage a tipping point whereby the cellular infiltrate from the chemokine-dependent response – now divorced from the synergistic and beneficial activation of the antiviral Type I IFN signalling pathway – begins to do more harm than good.

So can this detailed understanding of pathways explain the perceived variability in COVID-19 outcome? Jean-Laurent Casanova (HHMI, Rockefeller University) believes so, and highlights an association between inborn errors of Type I IFN immunity and life-threatening COVID-19, suggestive of an overly mild Type I IFN response as a risk factor in these vulnerable individuals. In addition, Jean-Laurent also reports on an association between auto-antibodies against Type I IFN and lethal COVID-19. Indeed as Jean-Laurent – a key member of the COVID Human Genetic Effort International Consortium – explains, “auto-antibodies to Type I interferon are observed in over 10% of patients with life-threatening COVID-19”. The core concept here is that neutralising auto-antibodies in these high-risk patients impair Type I IFN immunity, and render these patients particularly susceptible to COVID-19 disease complications.

Changes in the Blood: Reconfiguration of the Immune System in Severe COVID-19
So what additional changes in the blood do we observe in COVID-19 disease? Catherine Blish (Stanford University) and colleagues used single-cell RNA sequencing (scRNAseq) to profile severe COVID-19 and to address this question. By performing scRNAseq analysis on >40,000 peripheral blood cells from seven COVID-19 patients and six healthy controls, Catherine and her team observed a “massive reconfiguration of the immune system” in response to SARS-CoV-2 infection, with depletion of CD16+ monocytes, conventional dendritic cells, and NK (natural killer) cells in severe COVID-19 patients. As Catherine further explains, there is a reconfiguration of monocytes in COVID-19 with an observed upregulation of IFN-stimulated genes in the monocytes of COVID-19 patients relative to healthy controls, although Catherine is quick to point out that this response “is really heterogeneous”.

Catherine Blish’s talk.

It is interesting to ask whether this knowledge of the immune response helps us treat COVID-19? Ben tenOever highlights that enhancing our Type I IFN response is potentially one powerful means of combating the SARS-CoV-2 pathogen. In support of this, Ben highlighted that clinical trials of intranasal Type I IFN as a treatment for COVID-19 are now underway and that these clinical trials “look promising.”

For a playlist of all talks from this symposium please see the Human Cell Atlas YouTube channel.

For more details of recent research effort please see the Human Cell Atlas research on COVID-19.