Abstract
Dengue virus (DENV) is one of the most significant human viral pathogens transmitted by mosquitoes and can cause from an asymptomatic disease to mild undifferentiated fever, classical dengue, and severe dengue. Neutralizing memory antibody (Ab) responses are one of the most important mechanisms that counteract reinfections and are therefore the main aim of vaccination. However, it has also been proposed that in dengue, some of these class-switched (IgG) memory Abs might worsen the disease. Although these memory Abs derive from B cells by T-cell-dependent processes, we know rather little about the (acute, chronic, or memory) B cell responses and the complex cellular mechanisms generating these Abs during DENV infections. This review aims to provide an updated and comprehensive perspective of the B cell responses during DENV infection, starting since the very early events such as the cutaneous DENV entrance and the arrival into draining lymph nodes, to the putative B cell activation, proliferation, and germinal centers (GCs) formation (the source of affinity-matured class-switched memory Abs), till the outcome of GC reactions such as the generation of plasmablasts, Ab-secreting plasma cells, and memory B cells. We discuss topics very poorly explored such as the possibility of B cell infection by DENV or even activation-induced B cell death. The current information about the nature of the Ab responses to DENV is also illustrated.
Highlights
Dengue virus (DENV) is one of the most significant human viral pathogens transmitted by mosquitoes and causes every year ~390 million infections worldwide, resulting in around 500,000 people with severe dengue (SD)
We have shown the presence of E, precursor membrane (prM), and NS3 DENV proteins inside B cell follicles and germinal center (GC), indicating that DENV Ags are reaching draining lymph node (DLN) and raising the possibility that DENV might be even replicating in these lymphoid tissue compartments [50]
Conceivable, skin-infected dendritic cells (DC) might be ferrying DENV directly into DLNs [121]. All this would suggest that skin-derived DENV enters DLN via lymph and that at rather early stages, incoming DENV seems contained by macrophages in the subcortical area, a phenomenon described for other Ags such as Salmonella adelaide flagella [114]
Summary
Dengue virus (DENV) is one of the most significant human viral pathogens transmitted by mosquitoes and causes every year ~390 million infections worldwide, resulting in around 500,000 people with severe dengue (SD). Because M protein is first formed as a precursor called precursor M protein (prM), the maturation process of DENV is directed by the proteolytic cleavage of the prM, producing totally mature infectious particles [18,19,20] This mechanism is not completely efficient, and fully immature or partially mature virions are produced by host cells. It has been suggested that in the presence of non-neutralizing class-switched memory anti-prM Abs, even immature and non-infectious virus can enter to the cells via Fc gamma receptors (FcγR) and replicate efficiently, leading to more infected cells, potentially contributing to a more severe disease [23, 24]. The ideal DENV vaccine candidates should generate an optimal humoral response with Abs that bind to and neutralize the whole spectrum of viral structures [32]
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