Menu

Close

A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic

Maria Alimova, Eriene-Heidi Sidhom, Abhigyan Satyam, Moran Dvela-Levitt, Michelle Melanson, Brian T. Chamberlain, Seth L. Alper, Jean Santos, Juan Gutierrez, Ayshwarya Subramanian, Elizabeth Grinkevich, Estefania Reyes Bricio, Choah Kim, Abbe Clark, Andrew Watts, Rebecca Thompson, Jamie Marshall, Juan Lorenzo Pablo, Juliana Coraor, Julie Roignot, Katherine A. Vernon, Keith Keller, Alissa Campbell, Maheswarareddy Emani, Matthew Racette, Silvana Bazua-Valenti, Valeria Padovano, Astrid Weins, Stephen P. McAdoo, Frederick W.K. Tam, Lucienne Ronco, Florence Wagner, George C. Tsokos, Jillian L. Shaw, Anna Greka

Preprint posted on June 30, 2020 https://www.biorxiv.org/content/10.1101/2020.06.30.180380v1

and

Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

Willianne Hoepel, Hung-Jen Chen, Sona Allahverdiyeva, Xue Manz, Jurjan Aman, Amsterdam UMC COVID-19 Biobank, Peter Bonta, Philip Brouwer, Steven de Taeye, Tom Caniels, Karlijn van der Straten, Korneliusz Golebski, Guillermo Griffith, René Jonkers, Mads Larsen, Federica Linty, Annette Neele, Jan Nouta, Frank van Baarle, Cornelis van Drunen, Alexander Vlaar, Godelieve de Bree, Rogier Sanders, Lisa Willemsen, Manfred Wuhrer, Harm Jan Bogaard, Marit van Gils, Gestur Vidarsson, Menno de Winther, Jeroen den Dunnen

Preprint posted on July 13, 2020 https://www.biorxiv.org/content/10.1101/2020.07.13.190140v1

Two recent preprints indicate that Fostamatinib might help with severe COVID-19 symptoms and point to the importance of detailed examination of immune response to COVID-19 vaccines.

Selected by Yen-Chung Chen
Clinical manifestation and putative pathophysiology proposed in the preprints
Clinical manifestation and putative pathophysiology proposed in the preprints

Background and context

When seeking remedies for a poorly understood disease, there are two often-used strategies: one can first try to understand the disease and identify a treatable target. Alternatively, one can focus on the most severe disease outcomes, and then try to find some compound that could remove the disease’s fang.

While in the past six months our knowledge of the COVID-19 disease – and the causative agent SARS-CoV-2 – has grown, there is still a lot to learn in order to develop effective treatments. The virus was first reported to infect the respiratory system, but it also manifests neurological and gastrointestinal symptoms, suggesting possible invasion of other organ systems. The severity of the infection varies from no symptom or mild flu-like symptom to life-threatening respiratory failure and multiple organ failure.

Patients with severe COVID-19 often begin to deteriorate two weeks after contracting the disease. Two mechanisms could increase severity of the disease. First, there might be more virus in the body infecting and killing more cells. Second, the immune system might become more active, as indicated by the elevated level of cytokines in the blood. The overactive immune response could contribute to the potentially lethal symptoms, for example leading to respiratory epithelia secreting too much mucous that clogs the lungs, lung vasculature becoming compromised and leaky, and platelets and the coagulation cascade could be wrongly activated and result in blood clots that block blood vessels everywhere. All these contribute to the rapid deterioration of respiratory distress and the failure of multiple organs besides the lung, and eventually take the patient’s life in the worst-case scenario.

This highlight covers two preprints that used different strategies to find treatments for severely ill COVID-19 patients. Alimova et al. opted for a drug screening approach focusing on mucous secretion, while Hoepel and Chen et al. managed to clarify how SARS-CoV-2 elicits its clinical manifestation and identified a druggable target from the pathogenesis. Both preprints end up identifying the same molecule, a Syk inhibitor, as a candidate to treat severely ill COVID-19 patients.

Key findings

Screening for compounds that might alleviate respiratory symptoms

Alimova et al. suggested that the progress of respiratory failure could be slowed by attenuating mucous production, and set out to find compounds that might benefit severe COVID-19 patients. To this end, they designed a platform to screen for approved and non-toxic compounds that would attenuate mucous production.

Targeting Mucin-1, A gene associated with the severity of respiratory stress and mucous production

They selected Mucin-1 (MUC1) protein abundance as the readout in their screening. MUC1 is up-regulated in acute lung injury and correlates with the severity and recovery outlook. The authors identified several compounds that lower MUC1 expression in renal tubular cells, and then focused on one of the candidate compounds, Fostamatinib. They demonstrated that Fostamatinib does not impact cell viability and induces the down-regulation and internalization of MUC1. When administered to a mouse model of ischemia-reperfusion lung injury, Fostamatinib efficiently reduced the expression of MUC1 in the lung.

Searching for the culprit agitating the immune system of COVID-19 patients

Hoepel and Chen et al. first asked whether the dysregulated immune response accounts for rapid deterioration of severe COVID-19 patients. Previous studies have shown that multiple inflammatory cytokines are elevated in the blood of severe COVID-19 patients.

Antibodies with atypical modifications in the blood of severely ill COVID-19 patients trigger a cytokine storm

Hoepel and Chen et al. found that the presence of antibodies targeting the viral spike protein from patient blood triggers a cytokine storm in activated human macrophages. Then, they asked whether the antibody-induced cytokine storm explains the clinical manifestation of COVID-19. The authors showed that cytokines from patient serum-treated macrophages are sufficient to compromise vascular endothelial barrier and initiate blood coagulation, providing a mechanistic link between SARS-CoV-2 infection and clinical manifestation of COVID-19. What is so special about antibodies against the viral spike protein? The authors discovered that the fixed region of the spike-targeting antibody is distinctly glycosylated and mediates a cytokine storm via the Fc receptor gamma family.

An approved drug can block signaling under antibody recognition and attenuate cytokine storm

The activation of cytokine release can be attenuated by Fostamatinib, an inhibitor of Syk, which is a known downstream regulator of Fc receptor gamma signaling pathway.

Take-home message

Taken together, Alimova et al. and Hoepel and Chen et al. demonstrate that Fostamatinib, an FDA-approved drug, is a promising candidate for ameliorating severe COVID-19 in several ways. Alimova et al. showed that it could suppress MUC1 expression in the lung and might decrease mucous secretion during respiratory distress, while Hoepel and Chen et al. provide a pathophysiological framework of how SARS-CoV-2 infection leads to respiratory failure and multiple organ failure, and suggest that Fostamatinib can manipulate the pathogenesis of the disease to the patients’ advantage.

Why I like these preprints

It is a rewarding, yet difficult process to find out how a disease makes patients suffer and develop a way to treat it. The fortunate coincidence of two teams with very different mindsets and study design proposing the same drug as a potential treatment could be an excellent opportunity to compare and discuss the parallels of the works in order to strengthen the findings. It is amazing how Alimova et al. designed an efficient system focusing on MUC1 alone. Their clear designation of goal allows for rapid testing from cells to animal models. I also appreciate the grand scheme Hoepel and Chen et al. proposed, for it might provide the missing link to answer why this strain of coronavirus is unlike others and has become such a threat to public health.

Open questions

For Alimova et al.

  1. It seems to be a great leap from treating COVID-19 to targeting MUC1, which is more of a prognostic marker than a causative factor of respiratory failure. Proper goal selection is one of the difficult things that we repetitively encounter in research, and it would be great if you would share the story behind target selection with us.
  2. Considering that EGFR activation is central to mucous hypersecretion in respiratory diseases [1] and that steroids are shown to lower the mortality rate of severe COVID-19 patients in a recent clinical trial [2, 3], it is surprising that both inhibitors of EGFR and glucocorticoid agonists up-regulate the expression of MUC1. Does this implicate that MUC1 plays multiple roles in respiratory distress? If so, is there a recommended way to assess how good a treatment target MUC1 is given it serves multiple functions that have contradicting effects on disease progress?
  3. The down-regulation and translocation of MUC1 after Fostamatinib treatment shown in the preprint is intracellular. Considering MUC1 is also found in the bloodstream and associated with patient prognosis [4, 5], it is likely that MUC1 can also be secreted. I was thus curious if you have examined MUC1 presence in the medium for the cellular model to clarify whether the down-regulation is partially a result of secretion.

For Hoepel and Chen et al.

  1. While cytokine storm mediates severe cases of various viral infections like SARS, attenuating over-activation of the immune system is not always beneficial (for example, [6]). For example, immunosuppression might also delay the clearance of virus, which might outweigh the benefit of avoiding cytokine storm. To assess the pros and cons, I was curious if antiviral cytokines and interferons are also down-regulated with Fostamatinib treatment and whether there’s a way to assess if the treatment delays viral clearance or even worsens the infection.
  2. Following the previous question, immunosuppression, targeted or general, have shown promises for treating severely ill COVID-19 patients[6, 12], I was wondering if you have compared the efficacy of Fostamatinib to other compounds, like steroids or cytokine blocking antibodies.
  3. You showed that attenuating inflammation could prevent endothelial breakdown and thrombus formation. Considering that the immune system is always interacting with other tissues, and Alimova et al. showed that Fostamatinib treatment also suppresses MUC1, an anti-inflammatory mucin, in pneumocytes, it would be great if you could share your thoughts on whether the loss of MUC1 would offset the anti-inflammatory effect of a milder cytokine increase.
  4. Vaccine development is of great interest at the moment, and current published vaccine prototypes all use the spike protein as an antigen [7, 8, 9]. Considering that all three vaccines reported successful induction of antibody targeting the spike protein and that there are reports suggesting vaccine-induced antibodies could carry distinct glycosylation patterns [10, 11], it would be great if you would share you hunch on how much it would matter if vaccine-induced antibody carries the aberrant glycosylation pattern you mentioned in the preprint.

Special Thanks

  • Shu-Hung Kuo (Fellow of pulmonary and critical care medicine, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan) reviewed clinical remarks of COVID-19 and commented on the role of immunomodulation in COVID-19 treatment.
  • Dr. Máté Pálfy and Zhang-Ho Goh provided invaluable feedbacks and makes the highlight more comprehensible and precise.

References

  1. RECOVERY Collaborative Group. “Dexamethasone in Hospitalized Patients with Covid-19—Preliminary Report.” New England Journal of Medicine (2020).
  2. Kato, Kosuke, et al. “MUC1 contributes to goblet cell metaplasia and MUC5AC expression in response to cigarette smoke in vivo.” American Journal of Physiology-Lung Cellular and Molecular Physiology 319.1 (2020): L82-L90.
  3. Takezawa, Kumiko, et al. “Epidermal growth factor receptor inhibitor AG1478 inhibits mucus hypersecretion in airway epithelium.” American Journal of Rhinology & Allergy 30.1 (2016): e1-e6.
  4. Nakashima, T., et al. “Circulating KL‐6/MUC1 as an independent predictor for disseminated intravascular coagulation in acute respiratory distress syndrome.” Journal of internal medicine 263.4 (2008): 432-439.
  5. Nakashima, Taku, et al. “Mucins carrying selectin ligands as predictive biomarkers of disseminated intravascular coagulation complication in ARDS.” Chest 139.2 (2011): 296-304.
  6. Li, Huan, et al. “Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis.” Leukemia (2020): 1-9.
  7. Jackson, Lisa A., et al. “An mRNA Vaccine against SARS-CoV-2—Preliminary Report.” New England Journal of Medicine (2020).
  8. Folegatti, Pedro M., et al. “Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled tria” Lancet (2020)
  9. Zhu, Feng-Cai, et al. “Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial.” The Lancet (2020).
  10. Selman, Maurice HJ, et al. “Changes in antigen-specific IgG1 Fc N-glycosylation upon influenza and tetanus vaccination.” Molecular & Cellular Proteomics 11.4 (2012).
  11. Vestrheim, Anne Cathrine, et al. “A pilot study showing differences in glycosylation patterns of IgG subclasses induced by pneumococcal, meningococcal, and two types of influenza vaccines.” Immunity, inflammation and disease 2.2 (2014): 76-91.
  12. Calabrese, Cassandra, et al. “Practical aspects of targeting IL-6 in COVID-19 disease.” Cleveland Clinic journal of medicine (2020).

Tags: covid-19, cytokine storm, drug screen, fostamatinib, sars-cov-2

Posted on: 31st July 2020 , updated on: 3rd August 2020

doi: https://doi.org/10.1242/prelights.23323

(1 votes)




Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

preLists in the cell biology category:

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria

 



List by Gautam Dey, Samantha Seah

1

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka, Madhuja Samaddar, Miguel V. Almeida, Sejal Davla, Jennifer Ann Black, Gautam Dey

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Preprint missing? Don't hesitate to let us know.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

 



List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar, Ramona Jühlen, Amanda Haage, Laura McCormick, Maiko Kitaoka

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Gautam Dey

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

 



List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Gautam Dey

MitoList

This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

 



List by Sandra Franco Iborra

Biophysical Society Annual Meeting 2019

Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA

 



List by Joseph Jose Thottacherry

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.

 



List by Gautam Dey, Amanda Haage

Also in the pharmacology and toxicology category:

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

COVID-19 / SARS-CoV-2 preprints

List of important preprints dealing with the ongoing coronavirus outbreak. See http://covidpreprints.com for additional resources and timeline, and https://connect.biorxiv.org/relate/content/181 for full list of bioRxiv and medRxiv preprints on this topic

 



List by Gautam Dey, Zhang-He Goh

1

Drug use in special populations

Any drugs that are being used in special populations: Patients with liver and kidney failure, in paediatrics, in geriatrics, and in pregnant or lactating patients. Includes the discovery of factors that could potentially affect drug use in these special populations.

 



List by Zhang-He Goh

Toxicology of toxicants, existing therapeutics, and investigational drugs

Preprints that describe the toxicology of environmental pollutants and existing and upcoming drugs. Includes both toxicokinetics and toxicodynamics, as well as technological improvements that will help in the characterisation of this field.

 



List by Zhang-He Goh

Antimicrobials: Discovery, clinical use, and development of resistance

Preprints that describe the discovery of new antimicrobials and any improvements made regarding their clinical use. Includes preprints that detail the factors affecting antimicrobial selection and the development of antimicrobial resistance.

 



List by Zhang-He Goh

Anticancer agents: Discovery and clinical use

Preprints that describe the discovery of anticancer agents and their clinical use. Includes both small molecules and macromolecules like biologics.

 



List by Zhang-He Goh

Advances in Drug Delivery

Advances in formulation technology or targeted delivery methods that describe or develop the distribution of small molecules or large macromolecules to specific parts of the body.

 



List by Zhang-He Goh
Close