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

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.

Aedes Mosquito Salivary Components and Their Effect on the Immune Response to Arboviruses

“…In addition, infection of α/β-T cell deficient mice with JEV results in death over a 10- to 18-day period, in contrast to wildtype mice, which can survive infection, attributable to the granular lytic function of the cells (Jain et al, 2017 ). For DENV, lower percentages of regulatory B-cell subsets are associated with a more severe disease outcome during acute infection in humans (Upasani et al, 2019 ). Mosquito salivary factors have an effect on B- and T-cell responses and the proportion of these cell populations.…”

Autoantibody Profiling in Plasma of Dengue Virus–Infected Individuals

“…In patients infected with DENV, B cells show an activated phenotype leading to massive early plasmablast formation [ 8 , 11 , 51 ]. The current study demonstrates that eighty different IgM autoantibodies against complement components, coagulation factors and intracellular antigens were increased in patients infected with DENV compared to HD.…”

“…During the acute phase of infection, a rapidly expanding plasmablast population has been observed, where plasmablast frequencies are increased compared to other infectious diseases or after influenza or yellow fever vaccination [ 6 , 7 ]. In addition, frequencies of circulating plasmablast are associated to more severe dengue disease [ 8 ]. Here, DENV is capable to activate B cells directly inducing polyclonal and highly cross-reactive antibody generation after both primary and secondary infection [ 9 , 10 , 11 , 12 ].…”

Direct Infection of B Cells by Dengue Virus Modulates B Cell Responses in a Cambodian Pediatric Cohort

“…Infection with dengue virus has major impacts not only on the myeloid compartment in the blood but also on lymphoid cells (16). For example, it has been shown that circulating CD19 + cells are increased in dengue patients (17,18) and that their subset distribution is significantly altered during infection (19). For example, a massive increase in the frequencies of plasmablasts and plasma cells, reaching up to 50% of circulating B cells during the acute phase of infection has been reported (19,20).…”

“…For example, it has been shown that circulating CD19 + cells are increased in dengue patients (17,18) and that their subset distribution is significantly altered during infection (19). For example, a massive increase in the frequencies of plasmablasts and plasma cells, reaching up to 50% of circulating B cells during the acute phase of infection has been reported (19,20). Moreover, enhanced B cell activation and plasma cell development have been observed in hospitalized dengue patients compared to asymptomatic infected patients (21).…”