key: cord-0698698-0x7hcgtj
authors: Griffin, Justin H.; Downard, Kevin M.
title: Mass Spectrometry Analytical Responses to the SARS-CoV2 Coronavirus in Review
date: 2021-05-11
journal: Trends Analyt Chem
DOI: 10.1016/j.trac.2021.116328
sha: 2b69c4b3fbe06884341b7634a3ff7f2959e47bc0
doc_id: 698698
cord_uid: 0x7hcgtj

This article reviews the many and varied mass spectrometry based responses to the SARS-CoV2 coronavirus amidst a continuing global healthcare crisis. Although RT-PCR is the most prevalent molecular based surveillance approach, improvements in the detection sensitivities with mass spectrometry coupled to the rapid nature of analysis, the high molecular precision of measurements, opportunities for high sample throughput, and the potential for in-field testing, offer advantages for characterising the virus and studying the molecular pathways by which it infects host cells. The detection of biomarkers by MALDI-TOF mass spectrometry, studies of viral peptides using proteotyping strategies, targeted LC-MS analyses to identify abundant peptides in clinical specimens, the analysis of viral protein glycoforms, proteomics approaches to understand impacts of infection on host cells, and examinations of point-of-care breath analysis have all been explored. This review organises and illustrates these applications with reference to the many studies that have appeared in the literature since the outbreak. In this respect, those studies in which mass spectrometry has a major role are the focus, and only those which have peer-reviewed have been cited.

Just over a century from the 1918 influenza pandemic, warnings about a future viral pandemic have been realised with the emergence and spread of the SARS-CoV2 coronavirus. First detected in China in late 2019 [1] , the virus rapidly spread throughout the world and has currently been associated with over 2.5 million deaths and some 113 million cases of infection [2] , with Europe and the Americas particularly impacted. Beyond the global health emergency, the pandemic is estimated to have resulted in an economic cost exceeding $USD 10 trillion [3] , resulting from a decrease in the global economy of some 5%, only matched by the depression early in the twentieth century and the two world wars.

A global scientific effort has presented a united front to contain, monitor and respond to the virus through the implementation of a range of analytical, both molecular and nonmolecular, approaches. Chief among the technologies employed for the detection and surveillance of the virus has been reverse transcription-polymerase chain reaction (RT-PCR)-based analysis and sequencing [4, 5] . RT-PCR, quantitative PCR, Nucleic Acid Sequence-Based Amplification (NASBA), Loop Mediated Isothermal Amplification (LAMP), and CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) approaches have all been applied where some have potential for point-of-care diagnosis at the bedside [5, 6] .

Mass spectrometry has long been used for the study and analysis of viruses [7] [8] [9] [10] , though recent advances in instrumentation have offered improvements in sensitivity, resolution and mass accuracy, as well as the ability to analyse whole viruses and their interactions.

Some 200 publications describing the application of mass spectrometry, in some form, to characterise the coronavirus [11] have appeared in the literature since the outbreak of the pandemic and this review attempts to organise and review the approaches against J o u r n a l P r e -p r o o f conventional methods. It also explores the possibility of a frontline approach for point-ofcare diagnosis using a mass spectrometry platform technology.

J o u r n a l P r e -p r o o f 2.

SARS-CoV2 coronavirus, its structure and components, by the numbers A brief review of the nature of the SARS-CoV2 coronavirus is worthy of note since the subsequent mass spectrometric analysis is dependent upon it. The virus is a betacoronavirus whose genome is comprised of a single strand of RNA of some 30 kilobases in length. This contains 10 genes that encode 26 proteins, some from the cleavage of a polyprotein with proteases that are themselves part of that protein. In addition, an RNA polymerase and associated factors to copy the genome, a proof-reading exonuclease, and several other non-structural proteins are encoded [12] . The remaining genes code for structural components of the virus that comprise a surface spike (S) protein which binds host cell receptors [13] , a nucleocapsid (N) protein that packages the genome [14] and two membrane-bound (M) proteins that include the envelope (E) protein ( Figure 1 ). These are present in some 300 (S), 1000 (N), 2000 (M) and 20 (E) copies per virion with a diameter of some 100nm and a total mass of approximately 1 femtogram [15] .

The structural proteins have molecular weights of 141.2 (S -consisting of two subunits S1

and S2), 45.6 (N), 25.1 (M), and 8.4 (E) kDa. respectively [16] . The high copy numbers for the membrane and envelope proteins aid their detection by mass spectrometry, as does the sheer size of the surface spike protein particularly when detected in a digested form [16] . The spike protein adopts the form of a trimer on the surface of the virus where its two subunits (S1 and S2), generated by cleavage of the S protein at residues 685-686 and each approximately 70kDa. in size, catalyse the attachment of the virus to the membrane of a host cell and facilitate its fusion respectively.

Also of importance to mass spectrometric analysis is the viral copy numbers per isolate, CoV-2 in nasal swabs using MALDI-TOF MS aside conventional RT-PCR analysis was investigated [18] . In this study, MALDI mass spectra of nasal mucous secretion samples from three South American countries that had been confirmed either positive or negative for SARS-CoV-2 by RT-PCR. No report of the levels of virus in the secretion samples was made, but they can be expected to correspond to levels at or below those obtained from J o u r n a l P r e -p r o o f nasopharynx swabs (Figure 1 ). A total of 362 specimens (comprising 211 positive and 151 negative) were directly subjected to MALDI-TOF analysis and an intensity comparison was made based on seven selected peaks of distinct m/z values, mostly between 3000-3500 with one peak each at m/z 7612 and 10444. No effort to identify the biomarkers was made;

rather a principal cluster analysis (PCA) of the seven selected peaks using a machine learning approach was able to identify the presence or absence of SARS-CoV2 ( Figure   2A ) based upon detection of the ions and their relative mean intensities with 7% false positives and 5% false negatives. When PCA was performed with combined samples from the three laboratories, the results for the positive samples and negative controls did not completely resolve, though they did so when those of each laboratory were handled independently. Demonstrating a high degree of variability of detected components in the specimens, the study noted that among the selected peaks, only the m/z 7612 component (unidentified) was common to all spectra across all laboratories. The most substantial mean intensity difference was exhibited by ions at m/z 3358 that was best used to differentiate the control group from the SARS-CoV2 positive group.

A similar preliminary study of 311 patient specimens was conducted by Rocca et al. [19] .

The authors used the intensities of 10 peaks taken from the MALDI-TOF spectra and applied a machine learning algorithm and three difference classification models to assess its performance in detecting positive and negative SARS-CoV2 samples directly from nasopharyngeal swabs samples. Samples which exhibited six peaks at 3372, 3442, 3465, 3488, 6347 and 10836 Da. were used to assess the absence of infection based upon their reduced intensity or absence in the positive samples. An overall accuracy of some 68%

was reported (reflecting a positive prediction value of 60% and negative prediction value of 73.2% in the proportion of samples within cut-off parameters), but it was noted that none of the peaks found could be molecularly attributed to virus-specific proteins and were likely to some type of viral host components. and sample-to-sample reproducibility. Iles and co-workers [20] utilised the cold addition of acetone to precipitate viral protein from background host proteins and other contaminants where the pellet recovered after centrifugation was resuspended in a solubilisation buffer.

Low resolution MALDI-TOF of the S-protein subunits and their fragments, S1 (at ~ m/z 79000) and S2 (~ m/z 62000-72000) were detected together with other putatively identified viral-associated envelope protein fragments (ranging from ~ m/z 26000-47000) at elevated intensities in saliva and gargle samples of infected patients [20] ( Figure 2B ).

This, and the studies cited above, demonstrate the importance of higher resolution mass spectra to more confidently identify the components, particularly if intact viral proteins are to be identified. Furthermore, the establishment of a library of reference SARS-CoV2 viral protein mass spectra would enable one to perform a so-called biotyping experiment in which viral protein biomarkers could be assigned with more confidence. To circumvent this requirement, digested viral proteins can be detected at sufficient resolution to be identified on most MALDI-TOF based systems with reasonable reliability.

When high resolution mass accuracy is employed on a Fourier-transform based instrument (i.e. and ion cyclotron resonance (ICR) or Orbitrap), sufficient mass accuracy is obtained to allow viral peptides to be assigned unequivocally by mass alone ( Figure 2C ). In one such MALDI based study [16] , a whole virus digest detected across a mass range of m/z 500-3000 detected peptides of the nucleocapsid, membrane, and spike proteins with a J o u r n a l P r e -p r o o f typical sequence coverage of some 27%, or equivalent to that found by LC-ESI-MS [21] .

Mass accuracies exceeded 3ppm and a study of nasopharyngeal specimens found detection limits were better than 10 5 copies (compare with Figure 1 ) when using full scan mass spectra. Much lower limits are possible with selected ion monitoring. Importantly the ability to detect peptide ions unique to the virus by mass alone using high resolution mass spectrometry forms part of a proteotyping strategy applied to other respiratory viruses including influenza and parainfluenza [22] . time (up to several hours) per sample [21] , due to the LC run time and the need to wash and equilibrate the column after each run.

The use of a targeted strategy, in which selected peptide markers are detected together with their fragments in so-called parallel reaction monitoring (PRM), can help to reduce analysis times ( Figure 2D ). Cazares et al. [24] employed such a strategy in mock infected samples to detect peptides of the SARS-CoV-2 spike and nucleocapsid proteins. Four proteolytic peptides, two each from the spike and nucleoprotein, were selected based upon their reproducible production following digestion, and low limits of detection. Two such peptides were detected in PRM experiments in the ~200-400 attomole range following serial dilution of the samples. In such mock samples, this equated to the detection of virus at titre levels above some 2 × 10 5 pfu/mL (see Figure 1 ).

Gouveia and co-workers [25] utilised a similar procedure to identify a shortlist of 14 peptides derived from the matrix, nucleocapsid and spike proteins in a cell cultured SARS-CoV-2 virus sample, two of which matched those selected in the work of Cazares [24] . In a proof-of-concept study [26] , the same group acquired MS/MS spectra of peptides detected in two nasopharyngeal swabs but found only a small proportion of the peptide sequences could be mapped to microorganisms, raising concerns about false discovery rates. In simulated swabs containing specific quantities of SARS-CoV-2 virus, mixed with other nasal proteins, a single viral peptide of the nucleocapsid protein was reported at low ng or pfu level. An order of magnitude more material was needed to detect peptides from multiple proteins necessary for a more unequivocal analysis. Of nine positive clinical specimens, the authors detected virus peptides in two samples.

Another study by Singh and colleagues [27] , who also employed PRM, selected two peptides from the spike and a replicase polyprotein from a shortlist of eight peptides from these and the nucleoprotein. A detection sensitivity of 90% (from 57 of 63 samples) and

J o u r n a l P r e -p r o o f specificity of 100% in terms of RT-PCR confirmed positive samples was achieved. This study also reported the two peptides were detected in upper respiratory tract swabs of patients who have symptomatically recovered from SARS-CoV2 and had tested negative for RT-PCR analyses, demonstrating the potential of the MS approach to diagnosis asymptomatic SARS-CoV2 in patients. A larger study of close to 1000 specimens, employing the PRM strategy, detected peptides of SARS-CoV-2 nucleocapsid protein both qualitatively and quantitatively by incorporating 15N-labelled standards, in up to 84% of the positive cases with up to 97% specificity [28] . In this study, the use of a robotic sample handler enabled the analysis of 4 samples every 10 minutes.

A complementary strategy to the analysis of viral protein components is the implementation of mass spectrometry for the rapid detection of amplified polymerase chain reaction (PCR) products. This has been applied previously to a range of respiratory viruses [29, 30] using ESI [29] and MALDI based instruments [30] .

In the MALDI-TOF based study, serially diluted solutions of plasmids containing nearly the full-length sequence of target genes of human coronaviruses. The approach employed multiplex PCR, primer extension and MALDI-TOF identification of the amplicons. Virus was able to detect as low as 10 copies while the virus was detected in 22% (29/131) of clinical specimens using primers and extension probes specific to the RNA-dependent RNA polymerase (RdRp) and nucleocapsid (N) genes. The results were in accord with companion genomic analysis and PCR-sequencing.

In a more recent study, viral RNA was isolated and amplified from 44 nasopharyngeal or oropharyngeal swab specimens, that had tested either positive (22) or negative (22) if two or more amplicon targets were detected and negative if less than two were detected.

While the total run time for an exclusive RT-PCR analysis was considerably less than when combined with MS detection (some 80 versus 340 minutes), though both required a similar hands on intervention time [31] . The MS-based method also has a fast turnaround time from sample to diagnosis and therefore is suitable for routine use.

In the case of the SARS-CoV2 coronavirus, a particular focus has been on the study of the To resolve the site-specific glycosylation of the SARS-CoV-2 S protein and visualize the glycoform heterogeneity across the protein surface, one study purified recombinant SARS-CoV-2 S-protein using size exclusion chromatography to ensure the presence of nativelike trimeric protein [32] . This was then cleaved with three different proteases separately J o u r n a l P r e -p r o o f and the products analysed by LC-ESI-MS. The three proteases were selected to generate glycopeptides that contain a single N-linked glycan. A dispersion of oligomannose-type glycans was reported across both the S1 and S2 subunits. Whereas the glycan content (28%) was above that observed on typical host glycoproteins, it is lower than that for the envelope protein of HIV. This reduced glycan shield, it has been suggested [32] , may be of benefit in the elicitation of neutralizing antibodies when developing immunotherapies.

A second study [33] , which expressed the two subunits separately, identified the glycan As well as the complex heterogeneity seen at N-glycosylation sites, the study also identified two unexpected O-glycosylation sites within the receptor-binding domain (RBD) of the S1 subunit at residues Thr323 and Ser325. N-acetyl-galactosamine and neuraminic acid glycoconjugates predominated at the former residue, while N-acetylhexosamine and neuraminic acid glyconjugates were detected at the latter. Although the function of these glycosylation sites remains unknown, it was suggested that they may play a role in shielding protein epitopes and aid immunoevasion.

Another recent study [34] has investigated post-translational modifications in both the SARS-CoV2 surface protein and hACE2 provide additional structural details to study mechanisms underlying host attachment, immune response mediated by S protein and J o u r n a l P r e -p r o o f hACE2. All seven glycosylation sites in hACE2 were found to be completely occupied, mainly by complex N-glycans. However, this glycosylation did not directly contribute to the binding affinity between S-protein and hACE2 which was found to be impacted by The study further tested two translation inhibitors, ribavirin and NMS873, with different modes of action and found that these prevented viral replication.

Quantitative mass spectrometry, with and without the use of stable isotopes, has begun to reveal mechanisms underlying SARS-CoV-2 infection, including several key processes used by the virus to adapt their host. In a separate protocol, V'kovski and co-workers [38] adopted enzyme-catalyzed biotin-labelling of proteins within the coronavirus replicase J o u r n a l P r e -p r o o f transcriptase complex (RTC) that likely contribute to the viral life cycle using affinity purification and identification of biotinylated proteins by mass spectrometry ( Figure 2F ).

The metabolomics profiling of infected patients provides another means to better understand the underlying pathologic processes and pathways, and to identify potential diagnostic biomarkers. One study [39] adopted a targeted quantitative approach to analyze metabolites isolated from the blood plasma of infected patients using a healthy subjects [39] . Although the presence of plasma kynurenine effectively discriminated infected patients from healthy control subjects, further specificity was J o u r n a l P r e -p r o o f provided by a measure of the arginine/kynurenine ratio where arginine was found to be significantly depressed in infected patients. Arginine is an amino acid precursor for nitric oxide which increases blood flow and oxygen to wounds. Thus arginine is essential for tissue repair and its depletion could potentially delay and/or compromise ICU recovery.

The desire for a rapid, cost effective and non-invasive molecular test of SARS-CoV2 viral infections has awakened the role of breath analysis [40, 41] . The detection of volatile organic compounds (VOCs) by mass spectrometry has been active for several decades.

However, relatively little work has attempted diagnose viral infections using VOCs, since viruses hijack the host cell metabolism and, in so doing, do not produce their own metabolites [40] .

Various breath sampling devices are available and these can be taken by non-specialist staff. The key analytical aim is to detect elevated or reduced levels of VOCs at concentrations that are only a small percentage of exhaled carbon dioxide. GC-MS offers a sensitive and comparatively rapid approach with which to analyse breath samples ( Figure 4A) . A feasibility GC-ion mobility MS based study [42] involving 

Although the same mass resolution and accuracy is not achieved for the detection of whole virus particles ( Figure 2G ) and their complexes, there is merit in mass spectrometric based investigations. Ion mobility mass spectrometry offers an alternative to X-ray J o u r n a l P r e -p r o o f crystallography and cryo-electron microscopy in the study of virus assembly, composition, and heterogeneity as well as structural dynamics, despite its inability to provide the same level of structural detail of crystallographic studies.

Ion mobility mass spectrometry has been applied to study the binding of the receptorbinding domain of SARS-CoV2 spike protein with the ACE-2 host cell receptor [44] . A combination of molecular modelling IMS was used to investigate the role of heparin in destabilizing the RBD-ACE2 association.

The detection of both the monomeric (with a molecular mass of 33795 Da) and

homodimeric complex form of a protease of SARS-CoV2 virus has also shown in a preliminary communication [45] together with its dissociation constant. The unit, named the main protease, or M pro , is a cysteine protease that cleaves the encoded polyproteins at eleven sites resulting in a complex of twelve non-structural proteins (nsp5-nsp16).

However, the dissociation constant for SARS-CoV-2 M pro complex was determined by serial sample dilution and ion mobility mass spectrometry (MS) to be 0.14M, or over an order of magnitude lower than that obtained by analytical ultracentrifugation, raising caution about the native aspects of such experiments. The binding of several candidate small molecule inhibitors was undertaken with a view to assess their ability to bind to the dimer of SARS-CoV-2 M pro and inhibit the virus' ability to replicate.

Phylogenetic studies of viral protein evolution are another area where mass spectrometry is beginning to be applied. Mutations in the SARS CoV-2 virus are now becoming more as the world's population begins to be vaccinated, with those that help the virus to evade immune responses, vaccines and/or therapies are of most concern. It has been shown in a series of studies that have recently been reviewed [46] , that mass map profiles can be J o u r n a l P r e -p r o o f used to generate phylogenetic trees that are highly congruent with sequence based trees.

Importantly, the sequence-free mass approach can determine most common amino acid mutations from a pairwise comparision of mass differences alone that using a purpose built algorithm are also displayed at branch nodes across the tree. These so-called mass trees [47] allow the evolution of the protein, and the virus strain from which they were derived, to be charted and followed by tracing non-synonymous mutations patterns along interconnected branches. Ancestral and descendant mutations can be studied in the context of the origins of antiviral resistance or other evolutionary events.

A recent application of the approach examined the evolution of the SARS-CoV2 S-protein [48] . This is the subject of particular interest given the impact of mutations on the virus' transmissibility and virulence. Areas within predicted epitopes of high antigenicity are of particular concern in terms of the effectiveness of a universal vaccine. Mass maps for this protein across 27 strains of the virus were used to build the mass tree shown (Figure 5 box insert). Of the mutations shown on the tree (Figure 5 ), the algorithm correctly assigned all but four mutations. These outliers were present in peptide segments with one or two other mutations, such that a comparison of their mass differences did not correspond to a detectable single point mutation based on mass alone.

While RT-PCR based analyses continue to be the "gold standard" for the molecular surveillance and characterisation of the SARS-CoV2 virus, the approach is not immune to false positive and false negative results [49, 50] . In the real world, testing conditions are far from perfect, and accuracy suffers with higher false positive and negative rates. RT-PCR assays are typically complete within 2-4 hours, but this is after the specimens have been processed for analysis [51] , and detection limits down to some 10 copies of virus have J o u r n a l P r e -p r o o f been demonstrated [52] (Table 1) . Though amplification allows for the generation of extra copies, PCR sequencing is also necessary to monitor ongoing mutations in the SARS-CoV-2 genome, in part to decide whether the primers and probes designed remain suitable for the detection of mutated virus strains.

By comparison the direct analysis of viral proteins, or their peptide counterparts, with mass spectrometry is most challenged by the limit of detection. Studies reported in this review have consistently detected virus using MALDI and LC-ESI-MS approaches down to some 10 5 copies (Table 1 ). Even with the use of selected ion or reaction monitoring, only a magnitude or two improvement in sensitivity can be expected without other advances in detection capability. Thus, at best, without further advances in mass spectrometry technology at least one order of magnitude more material is required over RT-PCR analysis.

Similar detection limits restrict the application of the DNA amplicon detection by mass spectrometry [30] . 

The rapid and confident detection of a virus is a key requirement in an infectious disease outbreak such as that seen for the SARS-CoV2 pandemic. This detection needs to be both sensitive and be able to be performed by individuals with little training and expertise after appropriate inactivation of the virus [54] . including the identification of mutations that may limit detection by PCR or those that J o u r n a l P r e -p r o o f enable the virus to evade immune responses or challenge existing vaccines and/or therapies have great future potential. Without doubt, the expanded application of mass spectrometry and related "omics" strategies to better respond to virus outbreaks is sure to build on foundation studies [7] [8] [9] [10] 22 ] that predated the SARS-CoV2 pandemic. The growing reach of mass spectrometry into structural protein biology applications, using a range of approaches involving chemical and enzymatic treatments that have recently been compared side-by-side [55] , should also in our understanding of the virus, its molecular machinery and dynamics. Anatomy of the structure of the SARS-CoV2 coronavirus particle showing the structural proteins, copy numbers, virion size and mass, and infection sites and copies per typical specimen [15, 17] . All values are approximate only. (zoom) to view labels.

J o u r n a l P r e -p r o o f Table 1 Comparison of RT-PCR versus amplicon and viral peptide detection for SARS-CoV2 diagnosis J o u r n a l P r e -p r o o f Table 1 Comparison of RT-PCR versus amplicon and viral peptide detection for SARS-CoV2 diagnosis* step / parameter RT-PCR detection [5] DNA amplicon detection by MS [30, 31] * all times and figures are approximate only and depend on specific protocols and equipment employed. Citations are to representative studies ** according to real-time RT-PCR detection of SARS-CoV-2 protocol, Institut Pasteur, Paris (https://www.who.int/docs/defaultsource/coronaviruse/real-time-rt-pcr-assays-for-the-detection-of-sars-cov-2-institut-pasteur-paris.pdf) *** improve using immobilized enzyme digestion to 1-2 hours **** improve by one or two orders of magnitude with selected ion monitoring (SIM) J o u r n a l P r e -p r o o f 

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