Human dermal fibroblast-derived factors from sequential DENV-2 and ZIKV coinfection drive dendritic cell maturation...

Dengue virus (DENV) and Zika virus (ZIKV) are among the most prevalent mosquito-borne viruses worldwide. These viruses co-circulate in the same geographical regions and share the same mosquito vectors, enabling concurrent or sequential transmission to humans within a short period. During the early phase of arbovirus infection, skin-resident cells constitute the first line of defense following viral inoculation, yet the immunological events in the skin microenvironment during early DENV-ZIKV coinfection are not well understood. This study aimed to investigate the response of primary human dermal fibroblasts (HDFs) to DENV-ZIKV coinfection and to determine how these responses influence bystander immune cells within an in vitro. We demonstrated that sequential infection with DENV-2 followed by ZIKV significantly increased the expression of pro-inflammatory cytokines (IL-6, IL-8, IL-1β), leukocyte migration-associated chemokine (CXCL10), and antiviral mediators (IFN-β and IFN-λ) in HDFs. Primary monocyte-derived dendritic cells (moDCs) exposed to soluble mediators from sequentially coinfected HDFs exhibited greater activation marker expression compared with simultaneous coinfection or monoinfection conditions. Furthermore, these mediators conferred antiviral effects against both DENV-2 and ZIKV infection in treated moDCs. These findings highlight the important role of dermal fibroblasts in shaping adaptive immunity and limiting viral spread during DENV and ZIKV coinfection.