Correlation of host inflammatory cytokines and immune-related metabolites, but not viral NS1 protein, with disease severity of dengue virus infection

Abstract

Severe dengue can be lethal caused by manifestations such as severe bleeding, fluid accumulation and organ impairment. This study aimed to investigate the role of dengue non-structural 1 (NS1) protein and host factors contributing to severe dengue. Electrical cell-substrate impedance sensing system was used to investigate the changes in barrier function of microvascular endothelial cells treated NS1 protein and serum samples from patients with different disease severity. Cytokines and metabolites profiles were assessed using a multiplex cytokine assay and liquid chromatography mass spectrometry respectively. The findings showed that NS1 was able to induce the loss of barrier function in microvascular endothelium in a dose dependent manner, however, the level of NS1 in serum samples did not correlate with the extent of vascular leakage induced. Further assessment of host factors revealed that cytokines such as CCL2, CCL5, CCL20 and CXCL1, as well as adhesion molecule ICAM-1, that are involved in leukocytes infiltration were expressed higher in dengue patients in comparison to healthy individuals. In addition, metabolomics study revealed the presence of deregulated metabolites involved in the phospholipid metabolism pathway in patients with severe manifestations. In conclusion, disease severity in dengue virus infection did not correlate directly with NS1 level, but instead with host factors that are involved in the regulation of junctional integrity and phospholipid metabolism. However, as the studied population was relatively small in this study, these exploratory findings should be confirmed by expanding the sample size using an independent cohort to further establish the significance of this study.

Flavivirus NS1 and Its Potential in Vaccine Development

“…This is upheld by the discovery that the level of NS1 in serum samples does not correlate with the extent of vascular leakage, and the levels of host factors, such as cytokines, the adhesion molecule ICAM-1, and deregulated phospholipid metabolites, are elevated in those with severe disease. However, it should be noted that the study involved the analysis of only 40 samples [32]. DENV is unique in that it can induce hyperpermeability in endothelial cells from different tissues [33].…”

The acute effects of nonstructural-1 protein dengue virus type 2 on wet liver weight, zonulin expression and serum zonulin

“…So far, the mechanism of intravenous injection of NS1 increasing zonulin expression in the liver is unknown. Several studies indicated that NS1 increase the syntheses of proinflammation cytokines such as IL-1, TNF-α, IL-6, and IL-18 which induce the production of acute phase protein such as zonulin ( 12 , 39 – 42 ). Increased proinflammatory cytokines are known to occur in other viral infections such as COVID-19 ( 43 ).…”

Different Profiles of Cytokines, Chemokines and Coagulation Mediators Associated with Severity in Brazilian Patients Infected with Dengue Virus

“…Although it has been established that the circulating levels of NS1 antigen are positively correlated with DENV viremia [ 36 ] and are associated with severity [ 37 , 38 ], there is still debate about its usefulness as a biomarker [ 39 ]. In our study, no significant difference was found in the circulating levels of the NS1 antigen between the dengue patient groups.…”