For sequences analysis the following software packages were used: SeqScape (Applied Biosystems), ClustalX (Toby Gibson), Bio Edit (Tom Hall, Ibis Therapeutics), and Treeview (GubuSoft).  Tissue Tropism and Target Cells of NSs-Deleted Rift Valley Fever Virus in Live Immunodeficient Mice BACKGROUND: Rift Valley fever virus (RVFV) causes disease in livestock and humans. It can be transmitted by mosquitoes, inhalation or physical contact with the body fluids of infected animals. Severe clinical cases are characterized by acute hepatitis with hemorrhage, meningoencephalitis and/or retinitis. The dynamics of RVFV infection and the cell types infected in vivo are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: RVFV strains expressing humanized Renilla luciferase (hRLuc) or green fluorescent protein (GFP) were generated and inoculated to susceptible Ifnar1-deficient mice. We investigated the tissue tropism in these mice and the nature of the target cells in vivo using whole-organ imaging and flow cytometry. After intraperitoneal inoculation, hRLuc signal was observed primarily in the thymus, spleen and liver. Macrophages infiltrating various tissues, in particular the adipose tissue surrounding the pancreas also expressed the virus. The liver rapidly turned into the major luminescent organ and the mice succumbed to severe hepatitis. The brain remained weakly luminescent throughout infection. FACS analysis in RVFV-GFP-infected mice showed that the macrophages, dendritic cells and granulocytes were main target cells for RVFV. The crucial role of cells of the monocyte/macrophage/dendritic lineage during RVFV infection was confirmed by the slower viral dissemination, decrease in RVFV titers in blood, and prolonged survival of macrophage- and dendritic cell-depleted mice following treatment with clodronate liposomes. Upon dermal and nasal inoculations, the viral dissemination was primarily observed in the lymph node draining the injected ear and in the lungs respectively, with a significant increase in survival time. CONCLUSIONS/SIGNIFICANCE: These findings reveal the high levels of phagocytic cells harboring RVFV during viral infection in Ifnar1-deficient mice. They demonstrate that bioluminescent and fluorescent viruses can shed new light into the pathogenesis of RVFV infection. Rift Valley fever virus (RVFV) is an arthropod-borne member of the Bunyaviridae family, genus Phlebovirus that causes recurrent outbreaks affecting humans and animals. The virus can be transmitted by Aedes and Culex mosquitoes [1] , although it can also be transmitted by inhalation or physical contact with the body fluids from infected animals [2, 3] . Identified in the 1930s in Kenya, RVFV has spread during recent years to most sub-Saharan African countries, in Egypt and in the Arabian Peninsula, and in the Indian Ocean islands of Grande Comore and Mayotte [4, 5, 6] . In humans, RVFV infections are generally either asymptomatic or characterized by a feverish syndrome without any severe sequelae. However, a small percentage of patients exhibit complications, characterized by acute hepatitis with hemorrhage, meningoencephalitis and/or retinitis [7, 8, 9, 10] . A relationship has been demonstrated between high viral load in blood and death of the patient [11, 12] . RVFV infects domestic ruminants, including sheep, cattle, goats, and camels. It is responsible for massive abortion events in pregnant ruminants and high mortality in lambs and calves. High viremia associated with hepatic necrosis and increase of liver enzymes are hallmarks of severe acute lethal infection in ruminants [13, 14] . Encephalomyelitis has been described in calves [15] . Laboratory rodents such as mice are also highly susceptible to RVFV infection. In outbred Swiss mice, the survival time was inversely proportional to the logarithm of the viral dose inoculated via the intravenous route [16] . Depending on their genotype, males from various inbred strains of mice inoculated by the peritoneal route with 10 2 PFU of the virulent Egyptian ZH548 strain die between 4 to 10 days after inoculation, illustrating natural variation in susceptibility of the host to RVF [17] . The main damages of mouse infection with RVFV can be observed early in the liver, with extensive apoptosis of hepatocytes, accompanied in the blood by a peak in liver enzymes, along with increased bilirubin levels [18, 19, 20] . It has been recently shown that mice that survive hepatitis develop later infection of the brain, and eventually die from meningoencephalitis [21] . Interestingly, a diverse set of cell types from a number of tissues was found to contain RVFV antigens, including mononuclear phagocytes, but also cardiac myofibers, pancreatic islet cells, and adrenal medullary cells [21] . These data showed that RVFV exhibits a large tropism for a variety of tissues and individual cell types. Quantitative real-time PCR have also been used to study the kinetics of RVFV infection in the blood and organs of infected mice [22] . High amounts of RVFV RNA were found in blood, liver and brain samples shortly after infection with the highest viral RNA levels in the liver. We hypothesized that in vivo imaging might be an alternative method to assess viral replication using a recombinant RVFV carrying a reporter gene that allows the monitoring of viral expression in live animal.