Acute monocyte pro inflammatory response predicts higher positive to negative acute phase reactants ratio and severe hemostatic derangement in dengue fever

Choudhuri, Subhadip; Chowdhury, Imran H.; Saha, Avijit; Mitra, Bhaskar; Dastidar, Rinini; Roy, Pijush Kanti

doi:10.1016/j.cyto.2021.155644

Cited by 4 publications

(6 citation statements)

References 44 publications

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“…2 , differences in the retinal pigmented epithelium compared to macrophage responses in particular differing host responses in uninfected bystander MDM in the DENV-challenged population, or differences due to the primary nature of MDM compared to the immortalized ARPE19 cell line. Increased IL-6 has been associated with severe dengue in many studies ( 74 – 76 ), and results here suggest modulating Vav does not compromise control of DENV replication but may not benefit control of IL-6 production. In addition to inflammation and antiviral responses, Vav has a role in maintaining vascular integrity and the impact of Vav on DENV-induced changes to the endothelium remains to be defined ( 12 ).…”

Section: Discussionmentioning

confidence: 50%

Vav proteins do not influence dengue virus replication but are associated with induction of phospho-ERK, IL-6, and viperin mRNA following DENV infection in vitro

Cowell,

Jaber,

Kris

et al. 2024

Microbiol Spectr

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Vav proteins are guanine exchange factors that activate Rac1/RhoA signaling to regulate many biological processes including inflammatory responses. Here, the expression and functional significance of Vav’s were investigated during dengue virus (DENV) infection. In primary monocyte-derived macrophages, Vav1, −2, and −3 mRNA levels demonstrate variable responses to DENV infection and correlate with DENV-induced host inflammatory (IL-6 and TNF-α), antiviral (viperin), or cell adhesion [intercellular cell adhesion molecule (ICAM-1)] mRNA induction. Strong positive correlations were seen in particular for Vav2 with TNF-α and Vav3 with IL-6 mRNA. In the retinal pigmented epithelial cell line, ARPE-19, Vav2 was the main Vav expressed and was not affected by DENV infection. Heterologous Vav1 expression in ARPE-19 cells induced an increase in basal IL-6 mRNA but did not enhance DENV-induced mRNA responses. DENV RNA and DENV-induced viperin and IL-6 mRNA responses were also unaffected by Vav2 siRNA knockdown. Treatment of DENV-infected ARPE-19 cells with EHop-016 to block Vav signaling did not affect DENV RNA levels but increased DENV-mediated induction of IL-6 mRNA. More detailed assessment of DENV-induced responses to azathioprine, a clinically used immunosuppressant that can also block Vav signaling and act as a nucleoside analog, similarly demonstrated no change in DENV RNA levels but resulted in inhibition of DENV-induced phospho-ERK and increased DENV-induced-IL-6 and viperin mRNA in ARPE-19 cells. Thus, levels of Vav are associated with DENV-induced inflammatory responses, and blocking Vav signaling pathways does not compromise control of viral replication but may influence DENV-induced host responses. IMPORTANCE Dengue disease is characterized by an inflammatory-mediated immunopathology, with elevated levels of circulating factors including TNF-α and IL-6. If the damaging inflammatory pathways could be blocked without loss of antiviral responses or exacerbating viral replication, then this would be of potential therapeutic benefit. The study here has investigated the Vav guanine exchange factors as a potential alternative signaling pathway that may drive dengue virus (DENV)-induced inflammatory responses, with a focus on Vav1 and 2. While Vav proteins were positively associated with mRNA for inflammatory cytokines, blocking Vav signaling didn’t affect DENV replication but prevented DENV-induction of p-ERK and enhanced IL-6 (inflammatory) and viperin (antiviral) mRNA. These initial data suggest that Vav proteins could be a target that does not compromise control of viral replication and should be investigated further for broader impact on host inflammatory responses, in settings such as antibody-dependent enhancement of infection and in different cell types.

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Section: Discussionmentioning

confidence: 50%

Vav proteins do not influence dengue virus replication but are associated with induction of phospho-ERK, IL-6, and viperin mRNA following DENV infection in vitro

Cowell,

Jaber,

Kris

et al. 2024

Microbiol Spectr

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“…Similarly, studies by S. Chaudhary and Valero et.al. indicate no significant difference in serum ferritin levels between primary dengue infection and secondary dengue infection 12,40 . These findings suggest a strong correlation between serum ferritin levels and dengue disease severity and the onset of warning signs, irrespective of serotype specific infections, and primary or secondary dengue infections.…”

Section: Discussionmentioning

confidence: 77%

“…8 Hyperferritinemia is a hallmark characteristic of severe dengue and DwWS, although it can be observed in a wide range of inflammatory conditions and serves as an early predictor of onset in many diseases. [9][10][11][12][13] Ferritin is an acute phase reactant in both chronic and acute inflammation. It is an iron-binding protein produced by reticuloendothelial cells and regulates the iron flow in the circulation.…”

Section: Introductionmentioning

confidence: 99%

“…Elevated ferritin in dengue infection enhances neutrophils, lymphocytes, and macrophage‐mediated immune responses and increases the risk of developing complications with the severity of dengue illness 8 . Hyperferritinemia is a hallmark characteristic of severe dengue and DwWS, although it can be observed in a wide range of inflammatory conditions and serves as an early predictor of onset in many diseases 9–13 …”

Section: Introductionmentioning

confidence: 99%

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Serum ferritin level as a prognostic biomarker for predicting dengue disease severity: A systematic review and meta‐analysis

Shukla

Jadhav

Gurav

et al. 2023

Reviews in Medical Virology

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Serum ferritin levels serves as biomarkers in many inflammatory and infectious diseases. This current systematic review and meta‐analysis evaluated whether serum ferritin levels are associated with severe dengue and its utility as a biomarker of disease severity. Literature searches were conducted in PubMed, Scopus, ScienceDirect, the Cochrane library, and Google Scholar. A total of 18 studies examining the serum ferritin levels in dengue cases in the context of disease severity (nine studies having dengue classification as non‐severe vs. severe dengue cases, and nine studies having dengue classification as dengue without warning signs (DwoWS), dengue with warning signs (DwWS), and severe dengue cases) were included and the quality of the studies was assessed using the Quality in Prognostic Factor Studies tool. The meta‐analysis was performed using STATA software to calculate the effect size as a standardized mean difference (SMD) or Hedges ‘g’ for the continuous outcome. Higher serum ferritin levels were found in severe dengue cases compared to non‐severe cases [SMD (Hedges ‘g’) 4.05 (95% C.I. 2.09–6.00), (I2 = 98.8%)]. In the second group, DwWS cases showed high serum ferritin levels compared to DwoWS [SMD 2.01 (95% C.I. 0.92–3.10), (I2 = 97.89%)], and severe dengue cases showed higher levels of serum ferritin compared to DwWS [SMD 2.66 (95% C.I. 1.72–4.48), (I2 = 98.78%)] and DwoWS cases [SMD 6.65 (95% C.I. 1.72–11.59), (I2 = 99.78%]. Subgroup analysis for the country of study (India vs. others), ferritin testing methods, and ferritin measurement day revealed testing method as a significant contributor to heterogeneity. To conclude, the present study suggests serum ferritin as a prognostic marker for dengue disease severity. Multi‐centric studies involving a large number of dengue patients with a uniform case definition accounting for all the confounding variables might help in determining a universal cut‐off value to discriminate between non‐severe and severe dengue.

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“…Each year, almost 400 million people worldwide contract dengue, an acute viral febrile disease transmitted mainly by Aedes aegypti. Caused by dengue virus (DENV), it is one of the most widespread vector-borne infectious diseases in the world [1]. Belonging to the Flavivirus family, DENV is a single positive-stranded RNA virus comprised of four different serotypes [2,3].…”

Section: Introductionmentioning

confidence: 99%

Elevated Interleukin-37 Associated with Dengue Viral Load in Patients with Dengue Fever

et al. 2023

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Dengue remains a public health issue worldwide. Similar to chronic infectious diseases, stimulation of cytokine production is not enough to drive immune effector cells for effective virus clearance. One possible mechanism is the virus induces a large number of negative stimulatory cytokines inhibiting immune response. Interleukin 37 (IL-37) plays a crucial regulatory role in infection and immunity, inhibits innate and adaptive immunity as an anti-inflammatory cytokine by inhibiting proinflammatory mediators and pathways. To date, there are few studies reporting correlations between dengue fever (DF) and IL-37. In this study we found that the serum IL-37b and IL-37b-producing monocytes in patients were significantly increased in DF patients. A majority of the IL-37b produced by DF patients was produced by monocytes, not lymphocytes. Increased levels of IL-6, IL-10, and IFN-α were also found in DF patients. However, we failed to detect IL-1β, IL-17A and TNF-α in plasma, because of off-target. In our study, there was no relation between IL-6, IL-10, and IFN-α expressions and IL-37b in serum (P > 0.05). The IL-37b-producing monocytes were negatively correlated with the level of IFN-α in serum and platelet count, and positively correlated with lymphocytes percentage (P < 0.05, respectively). Additionally, serum DENV nonstructural protein 1 levels were positively correlated with monocytes percentages (P < 0.05). Our data represents findings for IL-37b expression and its potential mechanisms in DF patients’ immune response.

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Acute monocyte pro inflammatory response predicts higher positive to negative acute phase reactants ratio and severe hemostatic derangement in dengue fever

Cited by 4 publications

References 44 publications

Vav proteins do not influence dengue virus replication but are associated with induction of phospho-ERK, IL-6, and viperin mRNA following DENV infection in vitro

Vav proteins do not influence dengue virus replication but are associated with induction of phospho-ERK, IL-6, and viperin mRNA following DENV infection in vitro

Serum ferritin level as a prognostic biomarker for predicting dengue disease severity: A systematic review and meta‐analysis

Elevated Interleukin-37 Associated with Dengue Viral Load in Patients with Dengue Fever

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