Blood Proteome Profiling Of COVID-19 Patients Revealed Circulating Proteins MBL2, MMP3, IL2RA, FCGR2A, CCL5, GP1BA, VWF, ANG, SDC4 & CHL1

A new study by researchers from the KTH Royal Institute of Technology-Sweden, Karolinska Institutet-Sweden and Karolinska University Hospital Sweden involving the precise blood proteome profiling in an undiagnosed population with COVID-19 has revealed the following circulating proteins: MBL2, MMP3, IL2RA, FCGR2A, CCL5, GP1BA, VWF, ANG, SDC4 & CHL1.

 
Although self-sampled blood provided valuable information about the COVID-19 seroprevalence in the general population, an even deeper understanding of pathophysiological processes following SARS-CoV-2 infections was obtained by studying 276 circulating proteins that were quantified by proximity extension assays in dried blood spots (DBS).
 
Blood samples from undiagnosed individuals collected during the first wave of the pandemic were selected based on their serological immune response and matched on self-reported symptoms.
 
The study team stratified these as seropositive (IgM+IgG+; N = 41) or seronegative (IgM-IgG-; N = 37), and to represent the acute (IgM+IgG-; N = 26) and convalescent phases (IgM-IgG+; N = 40).
 
The study findings revealed proteins from a variety of clinical processes including inflammation and immune response (MBL2, MMP3, IL2RA, FCGR2A, CCL5), haemostasis (GP1BA, VWF), stress response (ANG), virus entry (SDC4) or nerve regeneration (CHL1).
 
The presented approach complements clinical surveys and enables a deep molecular and population-wide analysis of COVID-19 from blood specimens collected outside a hospital setting.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2021.11.15.21266315v1
 
Despite almost two years of the COVID-19 pandemic and extensive research, many aspects that could curb the pandemic remain unknown. The pathogen of this pandemic is the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has evolved with time, and some of the variants are more virulent with a higher rate of transmission and mortality rate.
 
SARS-CoV-2 infection affects an individual’s respiratory system and damages many other physiological systems, including cardiovascular, digestive, and nervous systems.
 
Many studies have found that one of the primary factors of COVID-19 pathogenesis is the over-activation of the innate immune response, which causes the cytokine storm.
 
Numerous past studies have helped understand the molecular mechanism behind SARS-CoV-2 infection or the factors contributing to severe infection. However, the long-term effects related to mild or asymptomatic COVID-19 infection are still not clear. Some studies using computed tomography revealed that even mild or asymptomatic infection could cause subclinical lung abnormalities.
 
Many medical researchers and scientists have highlighted the need for population-based studies to understand heterogeneous phenotypes, genetic and environmental factors, and their association with disease severity, mortality, and long-term effects of its health. Some large-scale population studies have been conducted, but their results contain biases.
 
/> Corresponding author, Dr Jochen M Schwenk from the Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology told Thailand Medical News, “The key problem in conducting large-scale population studies is proper sampling. Biased results may be obtained by including undetected or non-hospitalized individuals affected by COVID-19 infection with mild or no symptoms.”
 
In order to reduce bias, the study team have come up with a possibility to reach a population that is typically hard to reach, i.e., via home-sampled dried blood spots (DBS). Some of the advantages of the DBS system include the collection of samples without direct contact or requiring a skilled person.
 
Interestingly, this system also prevents visiting a healthcare center. The shortcoming of the DBS approach has recently been corrected by a new microfluidic-based DBS device that can collect the precise volume of blood in a controlled manner.
 
In the first pandemic wave, the study team used a volumetric DBS home-sampling device to collect 878 samples from Stockholm, Sweden, randomly.
 
The initial study helped determine the presence of IgG and IgM antibodies against several proteins from the SARS-CoV-2 virus in a multi-analyte assay.
 
The study team further collected DBS samples in the Stockholm population to conduct more analyses to understand the molecular effects of the infection.
 
For this study, the research team profiled 276 circulating proteins that are associated with cardiovascular and metabolic functions.
 
These proteins were present in the eluates previously prepared for the serological survey. The main focus of this study has been to gather a comprehensive picture of the biological processes along with the diverse immune responses associated with SARS-CoV-2 infection in a random population.
 
The research team claim that this study is the first proteomics survey conducted in a general population.
 
The key strength of this study is the integrity of the home sample that enabled obtaining high-quality molecular data with large cohorts.
 
The study team used proximity extension assays (PEA) for the proteomics analyses owing to their low sample volume requirement. PEA assays are also highly sensitive and specific.
 
Past studies have also used PEAs to quantify proteins from filter paper-based DBS samples collected from clinical settings.
 
The study validated the DBS sampling system by comparing the protein profiles generated using venous blood draw and DBS sample via finger pricking.
 
The study team found comparable results in both sampling systems. This study revealed that a higher abundance of protein was found in the DBS samples from the skin, intracellular, and blood cells due to cell lysis.
 
The study team conducted variability analysis and found that BLMH, THOP1, SOD1, and BAG6 are among the least variable proteins.
 
Importantly it should be noted that generally, assessment of circulating proteins helps monitor disease progression and determines the response to therapy in severely infected and hospitalized patients.
 
Furthermore, it also helps understand the causes behind the long-term symptoms experienced by the individuals affected with mild COVID-19 symptoms.
 
Past studies have reported that overproduction of pro-inflammatory cytokines causes multi-organ failure and increases levels of cardiac biomarkers such as Troponin, BNP, and MBL2, which are the predictors of mortality.
 
Interestingly when compared to seronegative individuals, those with mild symptoms showed high levels of MBL2, IL2RA MMP3, and FCGR2A protein, which were previously associated with ICU mortality.
 
Furthermore proteins, such as CRTAC and CHRDL2, involved with the active proliferation of cells and adaptive immune responses, were also found. The authors also indicated the presence of GP1BA, VWF, SDC4, ANG, and CHL1 in the sample.
 
The study team plans in the future to quantify stable proteins occurring at lower abundance, such as IL6 or TNF, and inflammatory biomarkers in circulation. Also, a more sensitive quantitative method is required to analyze proteins from DBS samples.
 
The study findings have provided valuable insights into the molecular effects of SARS-CoV-2 infection.
 
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