Protein disulphide isomerase A4 as a potential biomarker for coronavirus disease 2019: Correlation with cytokine profiles and disease progression

Abstract

This study investigated the role of protein disulphide isomerase A4 (PDIA4) in the pathogenesis of coronavirus disease 2019 (COVID-19), focusing on its relationship with disease severity and potential as a biomarker. We analysed a cohort of adult COVID-19 patients with varying disease severity, grouped by vaccination status. Serum levels of PDIA4 and cytokines (interleukin [IL]-6, interferon gamma inducible protein-10 [IP-10], IL-16, monocyte chemoattractant protein-1 [MCP-1], and platelet-derived growth factor-BB [PDGF-BB]) were measured using enzyme-linked immunosorbent assay and compared among patients with different disease severities. Statistical analyses were performed to assess the correlation between PDIA4 levels, disease severity, and inflammatory markers. Unvaccinated COVID-19 patients with pneumonia had significantly higher PDIA4 levels than those without pneumonia (517.94 ± 264 vs. 284.86 ± 2.24; p = 0.0022). Although unvaccinated patients requiring oxygen support exhibited higher PDIA4 levels than those not requiring oxygen (519.30 ± 269.67 vs. 420.89 ± 240.49; p = 0.4825), the difference was not statistically significant. No significant difference was observed in the PDIA4 levels between unvaccinated patients with and without respiratory failure. Levels of PDIA4 were positively correlated with the levels of IL-16, MCP-1, IP-10, and IL-6 (correlation coefficients: 0.28-0.62), although this correlation was weaker or absent in vaccinated patients. Our findings suggest that PDIA4 is associated with COVID-19 severity and may serve as a potential biomarker of disease progression. Further studies are needed to elucidate the mechanisms by which PDIA4 influences the immune response and assess its potential for therapeutic exploration in COVID-19.

Keywords: COVID-19; PDIA4; biomarker; cytokines; disease severity.

Figure 1.

Comparison of serum PDIA4 levels in COVID-19 patients (who have not received any COVID-19 vaccination) subgrouped based on (a) pneumonia diagnosis, (b) need for oxygen support, and (c) presence or absence of respiratory failure. *significant difference (p < 0.05).

Figure 2.

Comparison of serum IL-6, IP-10, IL-16, MCP-1, and PDGF-BB levels in COVID-19 patients (who have not received any COVID-19 vaccination) subgrouped based on: (a) pneumonia diagnosis (presence or absence of pneumonia) and serum IL-6 levels; (b) need for oxygen support (requirement or no requirement for oxygen support) and serum IL-6 levels; (c) presence or absence of respiratory failure and serum IL-6 levels; (d) pneumonia diagnosis (presence or absence of pneumonia) and serum IP-10 levels; (e) need for oxygen support (requirement or no requirement for oxygen support) and serum IP-10 levels; (f) presence or absence of respiratory failure and serum IP-10 levels; (g) pneumonia diagnosis (presence or absence of pneumonia) and serum IL-16 levels; (h) need for oxygen support (requirement or no requirement for oxygen support) and serum IL-16 levels; (i) presence or absence of respiratory failure and serum IL-16 levels; (j) pneumonia diagnosis (presence or absence of pneumonia) and serum MCP-1 levels; (k) need for oxygen support (requirement or no requirement for oxygen support) and serum MCP-1 levels; (l) presence or absence of respiratory failure and serum MCP-1 levels; (m) pneumonia diagnosis (presence or absence of pneumonia) and serum PDGF-BB levels; (n) need for oxygen support (requirement or no requirement for oxygen support) and serum PDGF-BB levels; (o) presence or absence of respiratory failure and serum PDGF-BB levels.

Figure 3.

Comparison of serum PDIA4 levels in COVID-19 patients (who have received COVID-19 vaccination) subgrouped based on (a) pneumonia diagnosis, (b) need for oxygen support, and (c) presence or absence of respiratory failure. *significant difference (p < 0.05).

Figure 4.

Comparison of serum IL-6, IP-10, IL-16, MCP-1, and PDGF-BB levels in COVID-19 patients (who have received COVID-19 vaccination) subgrouped based on: (a) pneumonia diagnosis (presence or absence of pneumonia) and serum IL-6 levels; (b) need for oxygen support (requirement or no requirement for oxygen support) and serum IL-6 levels; (c) presence or absence of respiratory failure and serum IL-6 levels; (d) pneumonia diagnosis (presence or absence of pneumonia) and serum IP-10 levels; (e) need for oxygen support (requirement or no requirement for oxygen support) and serum IP-10 levels; (f) presence or absence of respiratory failure and serum IP-10 levels; (g) pneumonia diagnosis (presence or absence of pneumonia) and serum IL-16 levels; (h) need for oxygen support (requirement or no requirement for oxygen support) and serum IL-16 levels; (i) presence or absence of respiratory failure and serum IL-16 levels; (j) pneumonia diagnosis (presence or absence of pneumonia) and serum MCP-1 levels; (k) need for oxygen support (requirement or no requirement for oxygen support) and serum MCP-1 levels; (l) presence or absence of respiratory failure and serum MCP-1 levels; (m) pneumonia diagnosis (presence or absence of pneumonia) and serum PDGF-BB levels; (n) need for oxygen support (requirement or no requirement for oxygen support) and serum PDGF-BB levels; (o) presence or absence of respiratory failure and serum PDGF-BB levels.

Figure 5.

To evaluate the correlation between PDIA4 and cytokines (IL-16, MCP-1, PDGF-BB, IL-6, IP-10), pearson correlation coefficients were calculated using GraphPad prism 10.1. Prior to conducting the correlation analysis, all data were checked for normality using the Shapiro-Wilk test. The coefficient values range from − 1 to + 1, where − 1 indicates a perfect negative correlation, +1 indicates a perfect positive correlation, and 0 indicates no correlation. A two-tailed p-value less than 0.05 was considered statistically significant. (*, p < 0.05; **, p < 0.01; ***, p < 0.001).