Dysregulated Serum MiRNA Profile and Promising Biomarkers in Dengue-infected Patients

Abstract

Objectives: Pathological biomarkers and mechanisms of dengue infection are poorly understood. We investigated a new serum biomarker using miRNAs and performed further correlation analysis in dengue-infected patients.Methods: Expression levels of broad-spectrum miRNAs in serum samples from three patients with dengue virus type 1 (DENV-1) and three healthy volunteers were separately analyzed using miRNA PCR arrays. The expressions of the five selected miRNAs were verified by qRT-PCR in the sera of 40 DENV-1 patients and compared with those from 32 healthy controls. Receiver operating characteristic (ROC) curve and correlation analyses were performed to evaluate the potential of these miRNAs for the diagnosis of dengue infection.Results: MiRNA PCR arrays revealed that 41 miRNAs were upregulated, whereas 12 miRNAs were down-regulated in the sera of DENV-1 patients compared with those in healthy controls. Among these miRNAs, qRT-PCR validation showed that serum hsa-miR-21-5p, hsa-miR-590-5p, hsa-miR-188-5p, and hsa-miR-152-3p were upregulated, whereas hsa-miR-146a-5p was down-regulated in dengue-infected patients compared with healthy controls. ROC curves showed serum hsa-miR-21-5p and hsa-miR-146a-5p could distinguish dengue-infected patients with preferable sensitivity and specificity. Correlation analysis indicated that expression levels of serum hsa-miR-21-5p and hsa-miR-146a-5p were negative and positively correlated with the number of white blood cells and neutrophils, respectively. Functional analysis of target proteins of these miRNAs in silico indicated their involvement in inflammation and cell proliferation.Conclusion: Dengue-infected patients have a broad “fingerprint” profile with dysregulated serum miRNAs. Among these miRNAs, serum hsa-miR-21-5p, hsa-miR-146a-5p, hsa-miR-590-5p, hsa-miR-188-5p, and hsa-miR-152-3p were identified as promising serum indicators for dengue infection.

Proof-of-concept study: profile of circulating microRNAs in Bovine serum harvested during acute and persistent FMDV infection

“…We also wanted to examine the differential miRNA profiles in serum from cattle infected with other viral pathogens; however, we were unable to find published reports comparable to the proof-of-concept study described herein. Despite that, the miRNA profiles generated from human serum collected from individuals infected with related + ssRNA viruses (Dengue virus and HCV) showed some dysregulated miRNAs shared with the ones reported for FMDV here, which included: let-7 g, miR-22-5p, miR-23b-5p, miR-146a, and miR-497 [51,52]. Of note, these shared miRNAs all are reportedly involved in the signaling pathways involved in cellular proliferation and apoptosis, from which it can be inferred that these pathways are important to life cycle of + ssRNA viruses.…”

Dengue NS5 modulates expression of miR‐590 to regulate ubiquitin‐specific peptidase 42 in human microglia

“…This piece of study is quite significant for the broad biomedical community who are pursuing various studies on viral pathogenesis. Earlier, dengue‐infected patients’ serum has displayed heavily dysregulated “fingerprint” microRNAs such as miR‐146, miR‐21, and miR‐590 . The role of miR‐146 and miR‐21 are quite known in regulation of early inflammatory pathways but function of miR‐590 was not explored to pinpoint its precise role in dengue pathogenesis.…”

“…Earlier, dengue-infected patients' serum has displayed heavily dysregulated "fingerprint" microRNAs such as miR-146, miR-21, and miR-590. 45 The role of miR-146 and miR-21 are quite known in regulation of early inflammatory pathways but function of miR-590 was not explored to pinpoint its precise role in dengue pathogenesis. Similarly, role of deubiqitinases in dengue viral pathogenesis is also poorly understood.…”

Mammalian microRNA: an important modulator of host-pathogen interactions in human viral infections

“…Further, these two miRNAs were correlated with number of leucocytes and neutrophils. These findings have suggested that miRNAs can also be employed as a diagnostic marker for DENV infection [90]. On the other hand, small viral RNA resembling miRNA found in mosquitos infected with DENV type 2 is reported to specifically target a viral gene and auto-regulates viral replication [91].…”