The Call of Coronal Duty
An insider’s perspective on the proteomic battlegrounds of COVID-19
Lauren Robertson | | Longer Read
With March 11, 2021 marking one year since COVID-19 was officially classified as a pandemic by the WHO, it goes without saying that many of us – not least those on the frontline of the fight – are feeling a bit war-weary. And yet, for so many in the scientific community who answered the call of duty back in 2020, the battle rages on.
With so much uncharted ground still to cover when it comes to this novel coronavirus and our response to it, there is an abundance of work ongoing across all disciplines of our field. For now, we decided to share some of the spoils from one battlefront in particular: proteomics. Here, experts Jeroen Demmers, Perdita Barran, and Manfred Wuhrer tell us about their work in the fight against COVID-19, and provide an insider’s perspective on some of the developments we can expect to see in the coming months.
How can proteomics help in the fight against COVID-19?
Understanding the role that proteins play in the SARS-CoV-2 infection process and disease progression is vital to the development of therapeutic and preventative strategies. In this way, proteomics has proven to be an indispensable tool in COVID-19 research, and its role will no doubt be expanded in the future.
Firstly, MS-based detection of SARS-CoV-2 proteins and their proteolytic peptides offers a simple and rapid virus detection assay. Using targeted proteomics, peptides of the SARS-CoV-2 nucleocapsid and spike proteins can be detected with high sensitivity and specificity in research samples and clinical specimens. This opens up the possibility of taking this technology to clinical diagnostic labs and turning it into point-of-care procedures as alternatives for nucleic acid-based methods, which could be particularly interesting from a cost-effective healthcare perspective.
Proteomics could also be used to develop approaches capable of predicting COVID-19 cases that might later progress into clinically severe disease. In fact, several studies have already identified potential protein biomarkers that are differentially expressed in COVID-19 patients and could be used to predict viral infection at early stages. (See the sidebar “Collaboration and Determination” to learn more about Perdita Barran’s work around targeted proteomics and biomarkers).
In other areas, investigation of the humoral antibody response to SARS-CoV-2 proteins has aided the development of antibody-based assays for diagnostic and therapeutic purposes. Recently, a comprehensive SARS-CoV-2 human protein–protein interaction map was generated using affinity-purification (AP) MS. Several hundreds of specific interactions between SARS-CoV-2 and host cell proteins were defined, and it was discovered that, for some of the involved human proteins, several existing FDA approved drugs were already available. Other proteomics-based research on the host cell response has shown that the complement system and metabolic pathways are severely affected in COVID-19 patients.
Unbiased, explorative proteomics has also been used to define the proteomes of autopsy samples from COVID-19 patients. For instance, it was shown that cathepsin L1, rather than ACE2, was significantly upregulated in the lungs of COVID-19 patients. In addition, systemic hyperinflammation and dysregulation of glucose and fatty acid metabolism was detected in multiple organs, which shows how the multi-organ proteomic landscape of such autopsies may help in our understanding of the biological basis of COVID-19 pathology.
Crosslinking MS has been used to study the interaction sites between antibodies and the spike protein in detail. Such studies, often combined with protein structure elucidation by tools such as cryo-EM are crucial in the development of antiviral therapeutics. In research studies, huge non-covalent assemblies of proteins – such as intact virus particles several tens of Megadaltons in mass – can be analyzed by MS. This way, conformational dynamics of viruses and viral proteins can be uncovered and this can yield valuable information on the stability and topology of macromolecular assemblies in general and virus capsid structure in particular.
Viral proteins, in particular those in the viral envelope (such as the spike protein), are extensively decorated by protein glycosylation. To understand how this post translational modification influences spike-ACE2 interactions with the host cell membrane, these glycan structures have been characterized in detail by (glyco)proteomics. Detailed analyses of the impact of emerging variants in spike and natural or designed-for-biologics variants of ACE2 on glycosylation and binding properties are important next steps in developing therapeutics.