Identification and Characterization at the Single-Cell Level of Cytokine-Producing Circulating Cells in Children With Dengue

Perdomo‐Celis, Federico; Romero, Felipe; Salgado, Doris M.; Vega, Rocío; Rodríguez, Jairo; Ángel, Juana; Franco, Manuel; Greenberg, Harry B.; Narváez, Carlos F.

doi:10.1093/infdis/jiy053

Cited by 12 publications

(9 citation statements)

References 38 publications

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“…In our dengue cohort however, we observed no alterations in granulocyte to lymphocyte ratio between severity groups. An earlier report also demonstrated synthesis of TNF-a, IL-6, and IL-10 from circulating B cells, monocytes, and mDC in PBMC of pediatric dengue patients; culture supernatants from these purified B cells activated allogeneic T cells (57). This study in a small cohort however, did not identify biomarkers of severity.…”

Section: Discussioncontrasting

confidence: 52%

Innate Immune Cytokine Profiling and Biomarker Identification for Outcome in Dengue Patients

et al. 2021

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BackgroundEarly biomarkers of progression to severe dengue are urgently required to enable effective patient management and control treatment costs. Innate immune cells, which comprise the earliest responders to infection and along with the cytokines and chemokines they secrete, play a vital role in orchestrating the subsequent adaptive immune response and have been implicated in the enhancement of infection and “cytokine storm” associated with dengue severity. We investigated the early innate immune cytokine profile of dengue patients during acute phase of disease in a prospective blinded study that included subjects with acute dengue and febrile controls from four major hospitals in Bengaluru, India along with healthy controls. We used intracellular cytokine staining and flow cytometry to identify innate immune biomarkers that can predict progression to severe dengue.ResultsDengue infection resulted in enhanced secretion of multiple cytokines by all queried innate immune cell subsets, dominated by TNF-α from CD56+CD3+ NKT cells, monocyte subsets, and granulocytes along with IFN-γ from CD56+CD3+ NKT cells. Of note, significantly higher proportions of TNF-α secreting granulocytes and monocyte subsets at admission were associated with mild dengue and minimal symptoms. Dengue NS1 antigenemia used as a surrogate of viral load directly correlated with proportion of cytokine-secreting innate immune cells and was significantly higher in those who went on to recover with minimal symptoms. In patients with secondary dengue or those with bleeding or elevated liver enzymes who revealed predisposition to severe outcomes, early activation as well as efficient downregulation of innate responses were compromised.ConclusionOur findings suggested that faulty/delayed kinetics of innate immune activation and downregulation was a driver of disease severity. We identified IFN-γ+CD56+CD3+ NKT cells and IL-6+ granulocytes at admission as novel early biomarkers that can predict the risk of progression to severity (composite AUC = 0.85–0.9). Strong correlations among multiple cytokine-secreting innate cell subsets revealed that coordinated early activation of the entire innate immune system in response to dengue virus infection contributed to resolution of infection and speedy recovery.

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Section: Discussioncontrasting

confidence: 52%

Innate Immune Cytokine Profiling and Biomarker Identification for Outcome in Dengue Patients

et al. 2021

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“…Accordingly, some HLA-A and B alleles [189,190,191,192,193], the timing of the T-cell response [67], the magnitude of their activation [46,194], and some of their effector molecules [195,196,197,198], have been associated with the development of severe dengue. Indeed, human T-cells are a major target of a multiplicity of stimulating factors and chemoattractants derived from monocytes, dendritic cells, and B-cells, inducing their massive activation during DENV infection [195,199,200,201,202,203]. Thus, serotype cross-reactivity of DENV-specific T-cells generated during primary infection, their exacerbated cytokine and lytic response inducing organ damage, competition with T-cells avid for the current infecting serotype, and enhancement of DENV infection of target cells, are mechanisms of the pathological role of T-cells during secondary DENV infections [204,205,206].…”

Section: Particular Characteristics Of the T-cell Response Againstmentioning

confidence: 99%

T-Cell Response to Viral Hemorrhagic Fevers

et al. 2019

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Viral hemorrhagic fevers (VHF) are a group of clinically similar diseases that can be caused by enveloped RNA viruses primarily from the families Arenaviridae, Filoviridae, Hantaviridae, and Flaviviridae. Clinically, this group of diseases has in common fever, fatigue, dizziness, muscle aches, and other associated symptoms that can progress to vascular leakage, bleeding and multi-organ failure. Most of these viruses are zoonotic causing asymptomatic infections in the primary host, but in human beings, the infection can be lethal. Clinical and experimental evidence suggest that the T-cell response is needed for protection against VHF, but can also cause damage to the host, and play an important role in disease pathogenesis. Here, we present a review of the T-cell immune responses to VHF and insights into the possible ways to improve counter-measures for these viral agents.

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“…Different human B cell subsets have been shown to exhibit regulatory functions such as CD24 hi CD27 + B10 cells (22), CD19 + CD24 hi CD27 int plasmablasts (23), and CD19 + CD24 hi CD38 hi transitional B cells (24) through the production of immunosuppressive cytokines IL-10 and TGF-β. In the context of DENV infection, not much is known about the antibody-independent B cell responses (25, 26).…”

Section: Introductionmentioning

confidence: 99%

Impaired Antibody-Independent Immune Response of B Cells in Patients With Acute Dengue Infection

Upasani

Ung

et al. 2019

Front. Immunol.

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Dengue is a mosquito-borne viral disease caused by dengue virus (DENV). The disease is endemic to more than 100 countries with 390 million dengue infections per year. Humoral immune responses during primary and secondary DENV infections are well-investigated. However, the impact of DENV infection on B cell subsets and their antibody-independent functions are not well-documented. Through this study, we aimed to define the distribution of B cell subsets in the acute phase of DENV infection and characterize the effect of DENV infection on B cell functions such as differentiation into memory and plasma cells and cytokine production. In our cohort of Cambodian children, we observed decreased percentages of CD24hiCD38hi B cells and CD27− naïve B cells within the CD19 population and increased percentages of CD27+CD38hiCD138+ plasma cells as early as 4 days post appearance of fever in patients with severe dengue compared to patients with mild disease. Lower percentages of CD19+CD24hiCD38hi B cells in DENV-infected patients were associated with decreased concentrations of soluble CD40L in patient plasma and decreased platelet counts in these patients. In addition, CD19+CD24hiCD38hi and CD19+CD27− B cells from DENV-infected patients did not produce IL-10 or TNF-α upon stimulation in vitro, suggesting their contribution to an altered immune response during DENV infection. In addition, CD19+CD27− naïve B cells isolated from dengue patients were refractory to TLR/anti-IgM stimulation in vitro, which correlated to the increased expression of inhibitory Fcγ receptors (FcγR) CD32 and LILRB1 on CD19+CD27− naïve B cells from DENV-infected patients. Collectively, our results indicate that a defective B cell response in dengue patients may contribute to the pathogenesis of dengue during the early phase of infection.

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Identification and Characterization at the Single-Cell Level of Cytokine-Producing Circulating Cells in Children With Dengue

Cited by 12 publications

References 38 publications

Innate Immune Cytokine Profiling and Biomarker Identification for Outcome in Dengue Patients

Innate Immune Cytokine Profiling and Biomarker Identification for Outcome in Dengue Patients

T-Cell Response to Viral Hemorrhagic Fevers

Impaired Antibody-Independent Immune Response of B Cells in Patients With Acute Dengue Infection

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