Abstract
Dengue is a worldwide expanding threat caused by dengue virus (DENV) infection. To date, no specific treatment or effective vaccine is available. Antibodies produced by plasma cells (PCs) might be involved concomitantly in protection and severe dengue immunopathology. Although a massive appearance of PCs has been reported during acute DENV infection in humans, this response has been poorly characterized. Here, we show the dynamic of PC generation in immune-competent mice cutaneously inoculated with DENV compared with two control experimental groups: mice inoculated with inactivated DENV or with PBS. We found that PC numbers increased significantly in the skin-draining lymph node (DLN), peaking at day 10 and abruptly decreasing by day 14 after DENV inoculation. Class-switched IgG+ PCs appeared from day 7 and dominated the response, while in contrast, the frequency of IgM+ PCs decreased from day 7 onwards. Even though the kinetic of the response was similar between DENV- and iDENV-inoculated mice, the intensity of the response was significantly different. Interestingly, we demonstrated a similar PC response to virus antigens (E and prM) by ELISPOT. In situ characterization showed that PCs were distributed in the medullary cords and in close proximity to germinal centers (GCs), suggesting both an extrafollicular and a GC origin. Proliferating PCs (Ki-67+) were found as early as 3-day postinoculation, and in-depth analysis showed that these PCs were in active phases of cell cycle during the kinetic. Finally, we found a progressive appearance of high-affinity neutralizing DENV-specific IgG further supporting GC involvement. Of note, these antibodies seem to be highly cross-reactive, as a large proportion recognizes Zika virus (ZIKV). The strong PC response to skin-inoculated DENV in this work resembles the findings already described in humans. We consider that this study contributes to the understanding of the in vivo biology of the humoral immune response to DENV in an immunocompetent murine model.
Highlights
Dengue virus (DENV) is an important viral pathogen affecting 390 million people worldwide yearly [1]
We have previously shown an increase in the size of draining lymph nodes (DLNs) and the induction of B cell responses following cutaneous DENV inoculation in immunocompetent mice [27, 29]
We looked for cells concomitantly expressing murine plasma cell (PC) markers CD138 and Ly6C [34] in DLNs by flow cytometry (Figure 1(b) and Figure S1)
Summary
Dengue virus (DENV) is an important viral pathogen affecting 390 million people worldwide yearly [1]. It has been suggested that one of the main risk factors for SD is the secondary infection with a heterologous DENV serotype [3,4,5,6]. While different factors like age, time period between infections, host genetic background, and virus serotype and isolates contribute to the disease outcome, the level and characteristics of preexisting anti-DENV antibodies have been associated with the severity of the disease [3, 7,8,9]. One of the leading hypotheses for this is the antibody-dependent enhancement (ADE) of DENV infection, where crossreactive sub- or nonneutralizing antibodies facilitate the entry, and the replication, of the virus in Fcγ receptor- (FcγR-) bearing cells [9,10,11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
