Zika virus spreads through infection of lymph node-resident macrophages

Zika virus (ZIKV) is an arthopod-vectored flavivirus that disseminates from the infection site into peripheral tissues, where it can elicit virus-induced pathology. To move through the body, ZIKV is thought to exploit the mobility of myeloid cells, in particular monocytes and dendritic cells. However, multiple distinct steps during viral spread culminate in peripheral tissue infection, and the timing and mechanisms underlying mobile immune cell shuttling of virus remain unclear. To understand the very early steps in ZIKV dissemination from the skin, we kinetically and spatially mapped ZIKV-infected lymph nodes (LNs), an intermediary stop en route to the blood. Contrary to dogma, migratory immune cells were not required for large quantities of virus to reach the LN or blood. Instead, ZIKV rapidly infected a subset of immobile macrophages in the LN, which shed virus through the lymphatic pathway into the blood. Importantly, infection of LN macrophages alone was sufficient to initiate viremia. Together, our studies indicate that sessile macrophages that live and die in the LN contribute to initial ZIKV spread to the blood. These data build a more complete picture of ZIKV movement through the body and identify an alternate anatomical site for potential antiviral intervention. HighlightsO_LIZIKV infects and replicates in distinct LN macrophage populations C_LIO_LILN macrophage infection results in infectious virus in the blood C_LIO_LIVirus reaches the blood in the absence of DC migration or monocyte infection C_LIO_LINodal macrophage infection does not sustain viremia or induce morbidity C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=74 HEIGHT=200 SRC="FIGDIR/small/508424v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@121bc33org.highwire.dtl.DTLVardef@1caf24borg.highwire.dtl.DTLVardef@e94a08org.highwire.dtl.DTLVardef@1fb6f62_HPS_FORMAT_FIGEXP M_FIG Caption: ZIKV infects lymph node macrophages, which shed infectious virus into the lymph and then blood. C_FIG