Vaccinia Virus Infection Inhibits Skin Dendritic Cell Migration to the Draining Lymph Node

Abstract

There is a paucity of information on dendritic cell (DC) responses to vaccinia virus (VACV), including the traffic of DCs to the draining lymph node (dLN). In this study, using a mouse model of infection, we studied skin DC migration in response to VACV and compared it with the tuberculosis vaccine Mycobacterium bovis bacille Calmette-Guérin (BCG), another live attenuated vaccine administered via the skin. In stark contrast to BCG, skin DCs did not relocate to the dLN in response to VACV. Infection with UV-inactivated VACV or modified VACV Ankara promoted DC movement to the dLN, indicating that interference with skin DC migration requires replication-competent VACV. This suppressive effect of VACV was capable of mitigating responses to a secondary challenge with BCG in the skin, ablating DC migration, reducing BCG transport, and delaying CD4 + T cell priming in the dLN. Expression of inflammatory mediators associated with BCG-triggered DC migration were absent from virus-injected skin, suggesting that other pathways invoke DC movement in response to replication-deficient VACV. Despite adamant suppression of DC migration, VACV was still detected early in the dLN and primed Ag-specific CD4 + T cells. In summary, VACV blocks skin DC mobilization from the site of infection while retaining the ability to access the dLN to prime CD4 + T cells.

Infection-induced lymphatic zippering restricts fluid transport and viral dissemination from skin

“…We therefore next asked whether scarification-induced lymphatic capillary zippering affects the generation of protective immune responses. Despite a reduction in fluid transport following VACV scarification and the inhibition of DC migration by replication competent VACV ( Aggio et al, 2021 ), DCs do access dLNs and drive potent protective immune responses ( Loo et al, 2017 ). We sought to quantify the impact of VEGFR2 signaling on DC migration.…”

Monkeypox: disease epidemiology, host immunity and clinical interventions

“…It has been postulated that infection of the dermal keratinocytes, fibroblasts and tissue-resident antigen-presenting cells such as monocytes, macrophages, Langerhans cells and dendritic cells might occur and migratory antigen-presenting cells could contribute to virus dissemination through the lymphatics 46 , 54 , 55 . Nonetheless, recent evidence from a mouse model of orthopoxvirus skin infection suggested that dendritic cell migration from the skin to draining lymph nodes is impaired on VACV 56 . The relocation of the virus from the skin to the lymphatics might also be supported by other mechanisms such as direct lymphatic vessel access, as observed in skin infection models of Zika virus 57 .…”

Cyclooxygenase-Derived Prostaglandin E2 Drives IL-1–Independent Mycobacterium bovis Bacille Calmette-Guérin–Triggered Skin Dendritic Cell Migration to Draining Lymph Node

“…Instead, infection is performed in the footpad skin to quantify relocation of skin DCs from that site to the dLN (the pLN). Prior results from the combined use of these models support the detection of TNF-α and IL-1α/β in infected skin with a role for TNFR-I and IL-1R-I in skin DC migration to dLNs ( 19 , 26 ). Indomethacin treatment had a visible, negative impact on BCG-mediated skin DC migration to dLNs ( Fig.…”

“…The mobilization of Ag-laden DCs from the infection site in the periphery to the dLN is needed for T cell priming. Support for this comes from observations, including our own, showing that failure or inhibition of skin DC migration from skin to dLN mutes the expansion of Ag-specific T cells in the dLN ( 19 , 26 – 28 ). The movement of DCs from tissue to LN is complex.…”