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Review 1: "Proteomics Analysis of Peripheral Blood Monocytes from Patients in Early Dengue Infection Reveals Potential Markers of Subsequent Fluid Leakage"

The reviewers highlight the potential relevance of the study in advancing knowledge regarding pathways involved in complicated dengue infection. Minor concerns were raised regarding the lack of validation of the study results with another methodology.

Published onMay 15, 2024
Review 1: "Proteomics Analysis of Peripheral Blood Monocytes from Patients in Early Dengue Infection Reveals Potential Markers of Subsequent Fluid Leakage"
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key-enterThis Pub is a Review of
Proteomics analysis of peripheral blood monocytes from patients in early dengue infection reveals potential markers of subsequent fluid leakage
Proteomics analysis of peripheral blood monocytes from patients in early dengue infection reveals potential markers of subsequent fluid leakage
Description

Abstract Infections caused by dengue virus (DENV) cause significant morbidity and mortality worldwide. The majority of patients have a mild course of dengue fever (DF) disease, however a proportion of infected individuals develop much more severe dengue haemorrhagic fever (DHF) resulting in circulatory collapse and multiorgan failure due to increased vascular permeability. Early detection of individuals likely to develop severe disease could lead to improved outcomes for patients, and help use healthcare resources more efficiently. At present there are no reliable markers during the earlier stages of infection that indicate which patients will go on to develop DHF. Our study was aimed at identifying proteins that are differentially regulated early during disease in peripheral blood monocytes (PBMC) of patients who subsequently develop DHF. Such proteins may also point at cellular pathways implicated in developing vascular leakage. PBMC were isolated from patients with a confirmed dengue infection, lysed and subjected to tandem mass tag mass spectrometry. One hundred and sixty proteins were differentially expressed in DENV-infected samples compared to healthy controls. These were mainly involved in type I interferon signaling, cytokine response, phagocytosis, haemostasis and cell adhesion. PBMC from DHF patients differentially expressed 90 proteins compared to individuals with DF; these were involved in down-regulation of platelet activation and aggregation, cell adhesion and cytoskeleton arrangement pathways. Proteins involved in oxidative stress and p38 MAPK signaling were upregulated in DHF samples during early infection compared to DF samples. The proteins reported here that are differentially regulated in PBMC early during infection could potentially serve as biomarkers to identify patients at risk of developing DHF at an early disease stage. This study also provides important observations on pathways implicated in severe DENV infection.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: Dengue is an important public health problem with an estimated of 390 millios of new infections annually. Prevalence of DHF varies from 6.3% in DENV-infected individuals (irrespective of symptoms) to 45.7% in symptomatic and hospitalized cases. Currently, there are not biomarkers for dengue severity. Highly enriched pathways in DHF were involved in negative regulation of macrophage activation and interleukin-8 production, as well as positive regulation of the p38MAPK cascade and ERBB signaling.

The manuscript by Perera et al. described the proteomics of peripheral blood monocytes (PBMC) isolated of patients with DF and DHF. The authors found one hundred and sixty proteins differentially expressed in DENV infected samples compared to healthy controls. These proteins were involved in type I interferon signaling, cytokine response, phagocytosis, haemostasis and cell adhesion. 

The experimental work is well-controlled and clearly described. However, I have some comments about the paper :

  • Currently, dengue is classified as dengue with or without warming signs and dengue severe, the authors using the classification of 1997 (WHO), could actualize the case definition.

  • The authors considered that the sample size used in this study is adequate or is a limitation of the work.

  • The authors report 160 differentially expressed proteins compared to the control and 90 proteins between the DHF and DF patients. The work is very descriptive, they do not verify by another methodology the differential expression of proteins in more patients to hypothesize that one of the proteins found may be a marker of severity.

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