Human immune cell engraftment does not alter development of severe acute Rift Valley fever in mice

<div><p>Rift Valley fever (RVF) in humans is usually mild, but, in a subset of cases, can progress to severe hepatic and neurological disease. Rodent models of RVF generally develop acute severe clinical disease. Here, we inoculated humanized NSG-SGM3 mice with Rift Valley fever virus (RVFV) to investigate whether the presence of human immune cells in mice would alter the progression of RVFV infection to more closely model human disease. Despite increased human cytokine expression, including responses mirroring those seen in human disease, and decreased hepatic viral RNA levels at terminal euthanasia, both high- and low-dose RVFV inoculation resulted in lethal disease in all mice with comparable time-to-death as unengrafted mice.</p></div

Weight change, survival, and viral RNA levels in RVFV-inoculated humanized mice.

<p>(A) Weight change (mean ± SD) and (B) survival in unengrafted NSG-SGM3 (NSGS) mice and Hu-NSG-SGM3 mice inoculated intramuscularly with 10⁴ TCID₅₀ (Hi) or 10¹ TCID₅₀ (Lo) of RVFV. Humanized mice were inoculated either 13 or 19 weeks (wk) post engraftment, as indicated. (C) Viral RNA genome copy number (per μL of RNA) normalized to 18S in blood, liver, spleen, and brain collected at time of terminal euthanasia (NSGS mice: 2–3 DPI for Hi or 3–4 DPI for Lo; Hu-NSG-SGM3 mice: 2 DPI for Hi or 3 DPI for Lo) determined by qRT-PCR (mean ± SD). Blood was obtained from all but 3 mice (Lo-13-wk-1 [ID 5082–15], and one mouse each in the Hi- and Lo-NSGS groups). Significant at confidence of *p ≦ 0.05 (NSGS vs. Hu-NSG-SGM3 at same dose); **p < 0.0001 (mean in liver of all groups vs. in spleen or brain).</p

Human and mouse cytokine expression in RVFV-inoculated humanized mice.

<p>Background control NSGS mice or Hu-NSG-SGM3 mice at 13 or 19 wk post engraftment were inoculated intramuscularly with 10⁴ TCID₅₀ (Hi) or 10¹ TCID₅₀ (Lo) of RVFV; samples were collected at terminal euthanasia (3 DPI for Lo; 2 DPI for Hi). Human (A) and mouse (B) cytokine expression in plasma of Hu-NSG-SGM3 determined by multiplex bead-based assays (mean ± SD). Illustrated is a subset of analytes that, in general, demonstrated the most pronounced increases in expression; complete human 25-plex and mouse 26-plex array data are available in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0201104#pone.0201104.s001" target="_blank">S1 Table</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0201104#pone.0201104.s002" target="_blank">S2 Table</a>, respectively. In addition to samples not obtained due to acute terminal disease, samples excluded due to insufficient volume from human cytokine analysis include Hi-13-wk-2 (ID 5083–08) and Hi-NSGS-2, and from mouse cytokine analysis Lo-13-wk-4 (5084–20), and Hi-13-wk-2 (ID 5083–08). Historical samples from mock-inoculated (control, open circles) Hu-NSG-SGM3 mice were used to determine baseline expression in both panels. Shading indicates areas outside of the dynamic range of the assay, as determined by the standard curve run in conjunction with samples.</p

Human immune cell reconstitution in mouse blood.

<p>Human cell engraftment assessed by flow cytometry 12 weeks post engraftment in all mice.</p

Single-dose replicon particle vaccine provides complete protection against Crimean-Congo hemorrhagic fever virus in mice

Single-dose replicon particle vaccine provides complete protection against Crimean-Congo hemorrhagic fever virus in mic