Abstract
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.
Highlights
Dengue is a mosquito-borne viral disease caused by dengue virus (DENV), a positive sense singlestranded RNA virus belonging to the Flaviviridae family
Frequencies of B cell subsets were compared between patients with confirmed DENV infection (n = 74) and those with febrile illness of other origin (n = 29) and further within DENV-positive patients between those with dengue fever (DF) (n = 52) and severe dengue (DHF/dengue shock syndrome (DSS)) (n = 22) classified according to WHO 1997 criteria [3]
No differences were observed in the memory cells (CD27+CD38−/lo), the percentages of antibody-secreting plasmablasts (CD27hiCD38hiCD138−) within the CD19+ B cell compartment was found to be significantly higher in DENV-positive patients compared to patients with other febrile illness (Figures 1C,D), which is surprising given the fact that these children are undergoing acute infections
Summary
Dengue is a mosquito-borne viral disease caused by dengue virus (DENV), a positive sense singlestranded RNA virus belonging to the Flaviviridae family. Clinical presentation of DENV infection can vary from asymptomatic infection with no apparent symptoms or mild dengue fever (DF), which is self-limiting to more severe forms of disease termed dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [3]. One theory proposed to explain this is termed as antibody-dependent enhancement (ADE) of infection [5, 6]. This theory postulates that serotype crossreactive antibodies can wane over a period of time and upon reaching non-neutralizing concentrations can increase infection by facilitating the FcγR-mediated endocytosis of DENV immune complexes into target cells such as dendritic cells, monocytes, and macrophages [7, 8]. Due to ADE and the search for crossserotype neutralizing antibodies, the humoral immune response to DENV has been a prominent research topic
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