To study the significance of virus replication in phagocytic cells in vivo, we injected intraperitoneally (i.p.) and intravenously (i.v.) clodronate-loaded liposomes (CLL) to Ifnar1-deficient mice prior to infection with RVFV. These liposomes are widely used to deliver clodronate to phagocytic cells, especially macrophages, and the accumulation of clodronate leads to irreversible metabolic damages, which will eventually result in apoptosis [45] . As reported previously [42, 43] , the i.p. administration of CLL kills macrophages in the peritoneum and spleen of wild-type mice whereas i.v. administration affects mainly macrophages in the spleen and liver. We first analyzed the effect of CLL treatment on the phagocytic cell population of the blood and spleen of Ifnar1deficient mice 24 h after i.p. and i.v. administration. Flow cytometric analysis was performed to compare the percentage of macrophages/monocytes, dendritic cells and granulocytes in samples from mice treated with CLL (N = 3) and PBS liposomes (PBSL) (N = 3). The CLL treatment resulted in a 23-fold reduction of CD11b + CD115 + cells (monocytes) and a 6-fold reduction of CD11b + F4/80 + -expressing macrophages in the blood and spleen, respectively. In addition, CD11b + CD11c + F4/80 2 cells (dendritic cells) were decreased 9-fold in the blood. By contrast, CD11b + CD11c 2 Ly6G + cells (granulocytes) were not depleted in the blood and spleen, as previously reported [46] . Altogether this analysis showed that, 24 h after CLL treatment, blood monocytes and dendritic cells and spleen macrophages were efficiently depleted in Ifnar1-deficient mice whereas granulocytes were not affected. Next, CLL-or PBSL-treated mice were infected intradermally with 10 4 PFU rZHDNSs-hRLuc at 24 h after liposome administration. To investigate whether the clodronate treatment affected viral replication in vivo, we first observed PBSL-and CLL-administered infected mice using the imaging of whole bodies at 24 and 40 h post-infection. The profile of bioluminescence signals was similar in PBSL-and CLL-administered mice (N = 5 in each group) (data not shown). However, we observed weaker signals in CLLadministered mice. Indeed, the signals in the liver region were on average fifteen and four-fold lower at 24 and 40 h post-infection respectively in CLL-administered mice compared to PBSLtreated mice (P,0.05). We then measured the viraemia at 24 