Research News: American Scientists Identify Blood Gene Signatures That Can Foretell COVID-19 Severity

Research News: Scientists from the NCH Healthcare System-Florida, University of South Florida and University of Illinois-Chicago in a new study have identified a specific set of genes associated with a poor prognosis of COVID-19.


 
Often poor outcomes after SARS-CoV-2 infection are difficult to predict. Survivors may develop pulmonary fibrosis.  The study team previously identified a 52-gene signature in peripheral blood, predictive of mortality in Idiopathic Pulmonary Fibrosis.
 
In this study, they analyzed this signature in SARS-CoV-2 infected individuals and identified genomic risk profiles with significant differences in outcomes.
 
Significantly, analysis of single cell expression data shows that monocytes, red blood cells, neutrophils and dendritic cells are the cellular source of the high risk gene signature.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.11.21.392670v1
 
SARS-CoV-2, the causative pathogen of COVID-19, has high infectivity and pathogenicity. Although a substantial proportion of SARS-CoV-2-infected individuals remain asymptomatic or mildly symptomatic, certain groups of individuals, such as elderly people or people with comorbidities, are highly susceptible to developing severe COVID-19.
 
The emergence of the COVID-19 pandemic has triggered many studies to be conducted to identify molecular and genetic risk factors that are associated with disease severity.
 
Importantly in this context, elevated blood levels and certain pro-inflammatory biomarkers, such as ferritin, C-reactive proteins and procalcitonin, have been shown to predispose COVID-19 patients to develop critical illness that requires mechanical ventilation. However, more studies are required to identify and characterize reliable biomarkers that can prioritize the best treatment options according to disease severity.
 
At present, according to the available literature, COVID-19 survivors are susceptible to developing pulmonary fibrosis, which is a pulmonary disease caused by damage and scarring of the lung tissue.
 
Taking this into consideration, the researchers had repurposed a 52-gene signature, which they had developed previously to predict the mortality risk of pulmonary fibrosis patients and to predict the clinical consequences of SARS-CoV-2 infection. https://pubmed.ncbi.nlm.nih.gov/24089408/
 
https://pubmed.ncbi.nlm.nih.gov/28942086/
 
For the study, of a set of 52 genes, the study team analyzed the expression of 50 genes using peripheral blood samples collected from SARS-CoV-2 patients. Moreover, they conducted single-cell expression analysis to identify the cellular sources of these genes.
 
The team excluded two non-coding RNAs as they were unavailable in some of the datasets.
 
Importantly of the 50 studied genes, 7 showed increased expression, and 43 showed reduced expression.
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The seven increased genes were PLBD1, TPST1, MCEMP1, IL1R2, HP, FLT3, S100A12) and the 43 decreased genes were  LCK, CAMK2D, NUP43, SLAMF7, LRRC39, ICOS, CD47, LBH, SH2D1A, CNOT6L, METTL8, ETS1, C2orf27A, P2RY10, TRAT1, BTN3A1, LARP4, TC2N, GPR183, MORC4, STAT4, LPAR6, CPED1, DOCK10, ARHGAP5, HLA-DPA1, BIRC3, GPR174, CD28, UTRN, CD2, HLADPB1, ARL4C, BTN3A3, CXCR6, DYNC2LI1, BTN3A2, ITK, SNHG1, CD96, GBP4, S1PR1, NAP1L2, KLF12, IL7R.
 
Utilizing a classification algorithm, the study team identified low-risk and high-risk genomic profiles.
 
The team observed that individuals with a high-risk genomic profile were significantly older and had a higher risk of developing severe COVID-19.
 
Significantly, the need for ICU admission or mechanical ventilation was significantly higher among them. The blood levels of lactate, C-reactive protein, and d-dimer were also significantly higher in people with a high-risk genomic profile compared to those with a low-risk genomic profile.
 
In order to identify the cellular sources of 50 genes, they conducted patient-level analysis using the classification algorithm, which had identified five low-risk and three high-risk genomic profiles.
 
Simply by comparing the proportions of different cell types between low-risk and high-risk profiles, the team  observed that individuals with high-risk profiles displayed higher proportions of red blood cells, monocytes, neutrophils, and dendritic cells.
 
It was also found that in contrast, higher proportions of T and B lymphocytes, natural killer cells, and antibody-producing plasmablasts were found in individuals with low-risk genomic profiles.
 
The detailed analysis of single cell data in SARS-CoV-2 infected subjects uncovered the cellular source of the 50-gene signature and pointed at CD14+ monocytes and neutrophils as critical cell types differentiating high versus low risk individuals.
 
Previous reports have shown that severe COVID-19 is marked by the occurrence of neutrophil precursors and increased circulating levels of CD14+ monocytes with high expression of alarmins S100A8/9/12 and low expression of HLA-DR. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405822/
 
The single cell analysis also confirmed the presence of increased number of neutrophil precursors, mature neutrophils and CD14+ monocytes with high expression of S100A12 and low expression of HLA-DPB1 and HLA-DBP1 as part of the high risk genomic profile.
 
The team had have previously shown increased circulating levels of CD14+ monocytes in IPF patients with a high risk genomic profile based on the 52-gene signature. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(18)30508-3/fulltext
 
The study team  also showed that increase circulating levels of CD14+ monocytes were predictive of transplant-free survival and mortality in IPF and other fibrotic diseases such as, scleroderma-associated interstitial lung disease (SSc-ILD), hypertrophic cardiomyopathy and myelofibrosis .

The single cell analysis also showed increased proportion of CD4 and CD8 T cells and Immunoglobulin producing plasmablast in individuals with a low risk profile, suggesting that strong T cell and distinct antibody responses may be responsible for milder COVID-19 infection seen in individuals with a low risk genomic profile. https://pubmed.ncbi.nlm.nih.gov/32728222/
 
https://pubmed.ncbi.nlm.nih.gov/32783920/
 
In order to further validate the data, the study team conducted cell-type-specific analysis using the classification algorithm, which had identified 46 high-risk and 109 low-risk genomic profiles. The findings revealed that red blood cells, neutrophils, monocytes, eosinophils, and dendritic cells comprised the high-risk profiles, whereas T and B lymphocytes, natural killer cells, and plasmablasts comprised the low-risk profiles.
 
The study findings indicate that T cell- and B cell-mediated robust immune responses may reduce the risk of developing a severe form of COVID-19.
 
The research findings indicate that the expression profiles of 50 genes in the peripheral blood can predict the clinical outcome of COVID-19 patients. The study also identifies the cellular sources of these genes. Taken together, important biomarkers identified in the study can be used to categorize COVID-19 patients based on their disease severity, which in turn can facilitate proper utilization of medical resources, including therapeutics and life-saving equipment. This can also reduce the risk and cost of unnecessary hospitalization.  
 
Also future studies correlating genomic risk profiles with immunophenotyping will be required to better understand the gene expression changes seen in subjects with a low risk genomic profile.
 
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