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B. Bioinformatics and . Hub, There was significantly more IFN?2 in the supernatants of MOPV-infected mDCs than those of LASV-infected mDCs. Chemokines (MCP-1, MCP-3, and IP-10) and growth factors (VEGF, G-CSF, and GM-CSF) were produced by MOPV-and LASV-infected mDCs. Many pro-inflammatory cytokines were also upregulated in both MOPV-and LASV-infected mDCs: IL-5, IL-6, IL-10, IL-12, IL-15, and TNF?. In our study, IL-6, IL-15, VEGF, and MCP-3 were particularly interesting, because they were produced in higher quantities by LASV-infected than MOPV-infected mDCs. Next, we used a transcriptomic approach to obtain an overview of mDC gene transcription. The differential expression of genes in MOPV-or LASV-infected mDCs relative to uninfected mDCs is presented in Fig 3B. The central column (MOPV/LASV) corresponds to the differential expression of genes between MOPV-infected mDCs and LASV-infected mDCs. The plotted genes show significant differences in expression between MOPV-infected mDCs and LASV-infected mDCs. Globally, genes up (or down) regulated in MOPV-infected mDCs relative to mock-infected mDCs were also up (or down) regulated in LASV-infected mDCs. However, the fold change of expression was generally higher for MOPV than LASV. Thus, the genes upregulated by MOPV were statistically more highly induced than those by LASV. As expected, many genes differentially regulated between MOPV-and LASV-infected mDCs were related to the immune response, IFN (IFN?6, IFN?8, IFN?10, and IFN?1), proinflammatory (IL15, IL15RA, SIGLEC7, and AXL), and cell-cell communication (CD101, CD200, HLA-W, MS4A4A, and HOMER3). We also identified genes involved in cell growth and death (Fas, BCL2L14, PRAME, and PID1), adhesion and mobility (SYNPO2, DMD, COL23A1, and VCAM1), or both (ANTXR1, AXL, and SDC2)

, Most of them were related to the immune response, showing that mDCs responded to both viruses. However, there were substantial differences between MOPV-and LASV-infected mDCs at the pathway level. Immunity-related pathways, such as Pattern Recognition Receptors or RIG-I Like Receptor signaling, were upregulated in MOPV-infected mDCs relative to LASV-infected mDCs (Fig 3C). DC maturation was also upregulated by MOPV relative to LASV. This difference was mostly caused by the upregulation of IFN-I, NF?B (p50), MDA5, and Fas genes in MOPV-infected mDCs, but not LASV-infected mDCs (S1D Fig). Overall, these results highlight differences in the activation state of MOPV-and LASV-infected mDCs

, At 2 dpi, IFN-I and CXCL10 were upregulated under both MOPV and LASV conditions (S4A Fig). MOPV-infected mDCs upregulated the activation markers CD40, CD80, CD83, and CD86 (48 hpi), but LASV-infected mDCs did not (Fig 4B). These results were 5 surprising, as they did not match those obtained with infected mDCs alone (Fig 1). Fig 4C shows the IFN-I response at 24 hpi for MOPV-and LASV-infected mDCs (mDC alone, results from Fig 1A) and mDCs in coculture (mDC-T coculture, results from Fig 4A), MOPV-infected mDCs, but not LASV-infected mDCs, activate T cells DCs are involved in the innate immune response. However, a major role of mDCs in vivo is to induce a specific cellular response. We developed a coculture model with mDCs (infected or not) and autologous T cells (CD4 and CD8)

, 80-(IFN?2) fold increase in IFN-I production relative to that of mock-infected cells when cocultured with T cells. Remarkably, coculture with T cells completely inhibited IFN-I synthesis by LASV-infected mDCs: alone, IFN-I production was comparable to that of MOPV-infected mDCs, and in coculture it was comparable to that of the mock condition. Altogether, these results show that mDC activation and the IFN-I response to MOPV were increased and prolonged in coculture, whereas activation and the IFN-I response to LASV were reduced and delayed. This suggests crosstalk between mDCs and T cells, MOPV infection of mDCs induced a 10-(IFN?1) to

, Ki67 expression by CD4 and CD8 T cells was also upregulated by MOPV-infected mDCs, suggesting their proliferation. Therefore, MOPV-infected mDCs induced activation, a cytotoxic response, and proliferation of CD4 and CD8 T cells. LASV-infected mDCs poorly activated T cells. We searched for factors that could influence the mDC response at early time points. The MOPV coculture was characterized by upregulation of IFN?, Fas ligand (FasL), IL-15, TNF?, and TRAIL (Fig 5E). None of these molecules were upregulated in the LASV coculture, and they may play a role in the modulation of mDC responses. Interestingly, IL-18 investigated the differences between the responses of MOPV-and LASV-infected mDCs in coculture, we assessed the role played by viral factors. We designed MOPV/LASV chimeras by swapping the different viral proteins between the viral backbones (Fig 6A). We obtained MOPV in which its GP, NP, or intergenic regions of the S segment (IGRS) were replaced by their LASV counterparts, and the corresponding LASV containing MOPV GP, Z, or IGRS. Successful exchanges of the ORFs were verified by next generation sequencing (S5 Fig) and western blot (S6A Fig). We also included LASV NP ExoN , an LASV mutant with a nonfunctional exonuclease domain in its NP, Lastly, we studied T cell responses in our model using flow cytometry. We quantified CD69, a marker of early T cell activation, 2 dpi (Fig 5A). CD69 was upregulated in both CD4 (Fig 5B) and CD8 (Fig 5C) T cells under conditions of MOPV infection, but not those of LASV infection

M. Wt, M. Gp-lasv, L. Np-exon, L. , L. et al., the IFN-I response was as low as under the uninfected condition. MOPV IGRS LASV-and LASV IGRS MOPV-infected mDCs produced small amounts of IFN-I and were designated as "intermediate". It is worth noticing that mDC activation by the chimeric viruses in mDC-T coculture did not match their attenuation on VeroE6 cells: LASV NP ExoN and MOPV NP LASV were the most attenuated ones, whereas their phenotypes in mDC-T coculture were completely different. These results confirmed that the differences we observed in the responses are due to the activity of viral proteins and not to defects in viral replication and assembly. The viral titers did not detectably increase over time for any of the viruses, We tested the chimeras in our mDC-T coculture model. Quantification of the IFN-I response allowed us to segregate the viruses into three groups: MOPV-like, LASV-like, and intermediate

, A549 cells were grown in DMEM supplemented with 0.5% penicillin-streptomycin, 5% FBS and 1% Hepes (all from Invitrogen). Mopeia (AN21366 strain [16]) and Lassa (AV strain [47]) viruses were grown in VeroE6 cells at 37°C, with 5% CO 2. Viral supernatants were harvested and used as the virus stock and the absence of mycoplasma was confirmed. LASV and MOPV titers were determined by plaque immunoassays as described below, VeroE6 cells were grown in DMEM supplemented with 0.5% penicillin-streptomycin and 5% fetal bovine serum (FBS, all from Invitrogen)

, We obtained LASV and MOPV chimeras by first generating plasmids coding for the S or L segment and depleted for an ORF (or intergenic region of the S segment, IGRS). Briefly, plasmids encoding the S or L segment were amplified with primers, (i) allowing the complete amplification of the plasmid, except the target ORF and (ii) flanked with BsmBI restriction sites downstream of the start and upstream of the stop codons of the deleted ORF, The reverse genetics systems of LASV and MOPV rely on a four-plasmid strategy, as described in [24], with the rescue procedure of recombinant viruses

, We used plasmids coding for the S segment of LASV or MOPV with a depleted NP (as described above). An insert containing the mCherry and NP ORFs, separated by a P2A self-cleavage site, was generated by overlapping PCR. This insert was cloned into the LASV?NP or MOPV?NP plasmid. MOPV and LASV with a FLAG-tagged Z protein were also obtained by reverse genetics, LASV-mCh and MOPV-mCh were modified to express the mCherry and LASV/MOPV NP proteins from a single gene

, IFN-I neutralization

, IFN? (MMHA-2, 2.5 ?g/mL), and IFN? (MMHB-3, 2.5 ?g/mL), all from PBL Assay Science. In the control condition, the cocktail contained corresponding control isotype antibodies, IgG1 (5 ?g/mL) and IgG2a (5 ?g/mL), both from or mCherryexpressing MOPV or LASV. For MOPV WT-and LASV WT-infected mDCs, small volumes of supernatant were harvested at various times post-infection and titrated. For mCherry-expressing MOPV and LASV, mCherry fluorescence was measured by fluorescence microscopy with Leica DMIRB. Virus titration Vero cells were infected with sequential dilutions of supernatant and maintained for six days with Carboxymethyl-cellulose (1.6%) (BDH Laboratory Supplies, DMEM supplemented with 2% FBS. Infectious foci were detected by incubation with monoclonal antibodies directed against MOPV and LASV (mAbs L52-54-6A, L53-2375 and YQB06-AE05, generously provided by Dr P. Jahrling, USAM-RIID, Fort Detrick, MD), followed by PAconjugated goat polyclonal anti-mouse IgG

, mDCs were isolated by negative selection using the Myeloid Dendritic Cell Isolation kit (Miltenyi Biotech). mDCs were maintained in RPMI 1640 Glutamax I, 0.5% penicillin-streptomycin, 10 mM HEPES, 1% nonessential amino acids (full RPMI), and 10% FBS (all from Invitrogen). mDCs were infected at a MOI = 2 or treated with pIC (Invitrogen) at 150 ?g/mL for a positive control of activation. For mDC-T cell coculture, autologous plasma (AP) was heated for 30 min at 56°C and centrifuged for 20 min at 1,200 x g before use. mDCs were isolated from 75 to 80% of the PBMCs (as described above) and T cells from 20 to 25%. For T cells, peripheral blood lymphocytes (PBLs) were isolated by centrifugation on 50% Percoll (GE Healthcare) in phosphate-buffered saline (PBS), PBLs were washed three times in full RPMI supplemented with 4% AP. B cells were depleted using CD19 antibodies coupled to immunomagnetic beads (Dynal). T cells and mDCs were maintained overnight in full RPMI supplemented with 1 mM sodium pyruvate (Invitrogen) and 10%

, Cellular genes expression was assessed using the Taqman Universal master mix and Taqman commercial primers and probes for FasL, IFN?6, IFN?8, IFN?, IL-15, IL-18, TNF?, TNF?, TRAIL, and CXCL10 (Life Technologies). For the IFN-I genes, we used the following primers and probes: 5'-GTGGTGCTCAGCTGCAAGTC-3' (sense), 5'-TGTGGGTCTCAGGGAGATCAC-3' (antisense) and 5'AGCTGCTCTCTGGGC-3' (probe) for IFN?1 ; 5'-CAGTCTAGCAGCATCTGCAACAT-3' (sense), 5'GGAGGGCCACCAGTAAAGC-3' (antisense) and 5'-ACAATGGCCTTGACCTT-3' (probe) for IFN?2 ; 5'TCTCCACGACAGCTCTTTCCA-3' (sense), 5'-ACACTGACAATTGCTGCTTCTTTG-3' (antisense) and 5'AACTTGCTTGGATTCCT-3' (probe) for IFN?. GAPDH mRNAs were amplified using commercial primers and probes, AP. mDCs were harvested and infected at a MOI = 1 for 1 h. Supernatants of uninfected vero cells were used for the mock condition. Infected mDCs were added to T cells at a ratio of one mDC to 10 T-cells

, Primers targeted MOPV NP (5'-CTTTCCCCTGGCGTGTCA-3' and 5'-GAATTTTGAAGGCTGCCTTGA-3') or LASV NP (5'-CTCTCACCCGGAGTATCT-3' and 5'-CCTCAATCAATGGATGGC-3'). We transcribed the pGEM plasmid, coding for fragments of the MOPV and LASV NP gene (including the sequence amplified by PCR), in vitro, using the Riboprobe in vitro Transcription System (Promega), to obtain RNA standards. Viral genomes were quantified (by copy number) by comparing our samples with sequential dilutions of these standards, viral RNAs were extracted from culture supernatants using the QIAamp Viral RNA Mini Kit (Qiagen)

, Transcriptomics mDCs were infected at a MOI = 1 by LASV or MOPV or were uninfected and incubated for 24 h at 37°C, 5% CO2. Cells were centrifuged and RNA from the cell pellets extracted using the RNeasy kit and DNAse I digestion (both from Qiagen), followed by a second DNAse digestion (Ambion), vol.6000, p.2100

. Bioanalyzer,

, Pair-end, 2x50 bp read-length illumina sequencing was performed on cDNA libraries, with a minimum of 30 million read pairs per sample. Pathway analysis was performed with Ingenuity Pathway Analysis software (QIAgen) and heatmaps were made using R. Flow Cytometry For mDC activation, mDCs were harvested 24 hpi, washed, and the pellets suspended in PBS complemented with 5% pooled human plasma. We incubated cells for 30 min at 4°C with Lin1-FITC, CD83(HB15e)-PE, CD40(5C3)APC-H7 (BD Bioseciences), CD11c(BU15)-PeCy5, CD86(HA5.2B7)-PeCy7, CD80(MAB104)-APC-AlexaFluor®750, HLADR(Immu-357)-KromeOrange

. For-mdc-t-coculture, The expression of intracellular proteins was analyzed by treating the cells with the FoxP3 Staining Buffer Set and FcR Blocking Reagent, human (Miltenyi Biotech), according to the manufacturer's instructions, and incubating them with Perforin(?G9)-FITC, CD69(FN50)-PeCy7, CD4(RPA-T4)-AlexaFluor®647, and/or CD8(RPA-T8)-BV421 (BD Biosciences

, For staining of intracellular virus, purified mDCs and mDC-T cocultures were harvested at 2, 5, and 8 dpi and centrifuged. The cell pellets were suspended in PBS complemented with 5% pooled human plasma and incubated for 30 min a 4°C with Lin1-FITC, CD11c(BU15)-PeCy5 and HLADR

. Kromeorange, Cells were treated with the FoxP3 Staining Buffer Set and FcR Blocking Reagent, human (Miltenyi Biotech), according to the manufacturer's instructions, and incubated with antiDYKDDDDK-APC antibody

, Western Blot VeroE6 cells infected with MOPV and LASV chimeras (MOI = 0.01) were lysed in Laemmli buffer (Bio-Rad) at 4 dpi. Heat-denaturated proteins were loaded and separated on 4-15% gradient precast gels and transferred onto PVDF membranes before staining. Samples were immunoblotted with primary antibodies against LASV GP1, LASV NP or LASV/MOPV Z, anti-mouse or anti-rabbit antibody conjugated to peroxydase (Jackson ImmunoResearch) and SuperSignal? West Dura Extended Duration Substrate (ThermoFisher Scientific). standard error of the mean (SEM) for each set of data were calculated using R. Graphs were generated using SigmaPlot, The fluorescence of paraformaldehyde-fixed cells was measured using an EPICS-XL flow cytometer

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, Cells positive for activation molecules were counted. Results are expressed as the percentage of positive CD4 (C) or CD8 (D) T cells. Data shown are the means and SEM of seven independent experiments. (E) Quantification of mRNA is expressed as the gene/GAPDH ratio. Data shown are means and SEM of four independent experiments, Dot plot showing expression of CD69 in CD3 + cells 2 dpi. CD8 + cells correspond to CD8 T cells and CD8-cells to CD4 T cells. (B)

, In the schematic views, the black segments correspond to MOPV elements and grey segments to LASV elements. LASV NP ExoN has mutations in the NP exonuclease domain that make it nonfunctional. MOPV IGRS LASV and LASV IGRS MOPV have exchanged intergenic regions of the S segment. The images show the plaque phenotypes of the viruses. (B-C) mDCs were infected with wild type (WT) or chimeric viruses (MOI = 1) or were uninfected and cultured with T cells for one or two days. (B) Fold change between 1 and 2 dpi in intracellular viral RNA levels (log2([RNA copy per cell at 2 dpi]/[RNA copy per cell at 1 dpi]). (C) Quantification of IFN-I mRNA at 1 dpi is expressed as the gene/GAPDH ratio. Black and grey bars correspond to viruses with the MOPV and LASV backbones, respectively. Data shown are the means and SEM of four independent experiments. Statistical significance was assessed by the non-parametric Wilcoxon test and infected with WT or chimeric viruses (MOI = 1) or were uninfected and cultured with T cells for 1, 2, Fig 6. Exchanging viral proteins between MOPV and LASV modifies mDC activation in the context of mDC-Tcell coculture. (A)

, Cells positive for activation molecules were counted. Results are expressed as the percentage of positive CD4 (A) or CD8 (B) T cells. Black and grey bars correspond to viruses with the MOPV and LASV backbones, respectively. Data shown are the means and SEM of four independent experiments. Statistical significance was assessed by the non-parametric Wilcoxon test, + /CD4 + cells (A) and CD8 T cells as CD3 + /CD8 + cells (B)

L. Fig, Quantification of IFN-I and TNF? mRNA was normalized to GAPDH expression. Data plotted are the fold change in MOPV-infected mDCs relative to uninfected mDCs. (B-C) mDCs were cultured for 24 h with MOPV or LASV (MOI = 2). Viral genomes in culture medium (B) or cell pellet (C) were quantified by RT-qPCR. (D) mDCs were cultured for 24 h with culture medium (mock), MOPV, or LASV (MOI = 1). Cellular mRNAs from three independent experiments were quantified using poly-A amplification and next-generation sequencing. Data shown are the differential expression of genes from the "dendritic cell maturation" pathway (from Ingenuity Pathway Analysis), Genes

, Culture medium (A) was collected at day 2, 5, 8 and 12 post-infection, and cells (B) were collected at day 1, 2, 5, 8, 12 and 15 postinfection. Viral genomes in culture medium (A) or cell pellets (B) were quantified by RT-qPCR. (C) mDCs were infected with Z-tagged MOPV or LASV (MOI = 1) or uninfected (mock), and cultured with or without T cells (mDC alone and mDC in coculture ,respectively). 2, 5 or 8 dpi, mDCs positive for the Z protein were quantified by flow cytometry. A549 cells infected with Z-tagged MOPV or LASV (MOI = 0.1) for 1 or 2 days were used as a control. S3 Fig. MOPV and LASV infection of T cells For the "LT in coculture" condition, mDCs were infected with Z-tagged MOPV or LASV (MOI = 1) or uninfected (mock), and cultured with T cells, Fig. MOPV and LASV infection of mDCs in coculture with T cells (A-B) mDCs were infected with MOPV or LASV (MOI = 1) and cultured with T cells

. Fig, Evolution of mDC-T cell coculture over time. (A) mDCs were infected with MOPV or LASV (MOI = 1) or were uninfected and cultured for 48 h with T cells. Quantification of IFN-I and CXCL10 mRNA is expressed as the gene/GAPDH ratio

, Cells positive for activation molecules were counted. Results are expressed as the percentage of positive CD4 (B) or CD8 (C) T cells. Data shown are the means and SEM of seven independent experiments. Statistical significance was assessed by the non-parametric Wilcoxon test and differences were considered to be significant for p < 0.05 (*), + /CD4 + cells (B) and CD8 T cells as CD3 + /CD8 + cells (C)

, A-B-C) VeroE6 cells were infected with wild type and chimeric viruses (MOI = 0.01) for 4 days. (A) Cells were lysed 4 dpi, and viral proteins were detected by western blot. The anti-GP antibody only recognizes LASV GP1. The anti-NP antibody better recognizes LASV NP compared to MOPV NP. The anti-Z antibody recognizes both LASV and MOPV Z. (B) Culture medium was collected from 0 to 4 dpi and viral titers were determined. Data shown represent the mean ± SE of 3 independent experiments. (C) Viral genomes in the culture medium were quantified by RT-qPCR 4 dpi. Data shown represent the mean ± SE of the viral genomes/viral titer ratio for 4 independent experiments. Black and grey bars correspond to viruses with the MOPV and LASV backbones, respectively. (D) mDCs were infected with wild type and chimeric viruses (MOI = 1) and cultured with T cells. Culture medium was collected at day 2, 5, 8 and 12 post-infection, and viral titers were determined. Data shown represent the mean ± SE of 3 independent experiments. S7 Fig. Gating of mDCs and T cells by flow cytometry. (A) Gates used to identify purified mDCs (Fig 1B). Data shown here are for uninfected mDCs at 24 hpi. Part of the debris was eliminated on FSC-SSC (cells). SSCint/SSCtof was used to exclude doublets (single). Among the "single" gated cells, mDCs were gated as Lin1-/HLADR + cells. Lin1-/HLADR-contained mostly debris. Contaminating cells (Lin1 + ) represented less than 25% of the cells in all experiments and were mainly monocytes, ORF exchanges between MOPV and LASV VeroE6 cells were infected with wild type and chimeric viruses (MOI = 0.01) for 4 days. Culture medium was collected and the natures of the viral stocks were determined by next generation sequencing. Data show the coverage of the obtained sequences, using MOPV (A) or LASV (B) genome as a reference. S6 Fig. Characterization of MOPV and LASV chimeras

, Among the "single" gated cells, mDCs were gated as Lin1/HLADR + cells. (C) Gates used to identify CD4 and CD8 T cells in mDC-T coculture (Fig 4B). Data shown here are for uninfected cocultures at 48 hpi. Lymphocytes (Lympho) were selected

, SSCint/SSCtof was used to exclude doublets (single)

, + /CD4 + cells (lower right panel). CD8 T cells were gated as CD3 + /CD8 + cells, and Natural Killer cells (NK) as CD3-/CD8 + cells