Secreted NS1 proteins of tick-borne encephalitis virus and West Nile virus block dendritic cell activation and effector functions
ABSTRACT The flavivirus non-structural protein 1 (NS1) is secreted from infected cells into the circulation and the serum levels correlate with disease severity. The effect of secreted NS1 (sNS1) on non-infected mammalian immune cells is largely unknown. Here, we expressed recombinant sNS1 proteins...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-10-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.02192-23 |
| _version_ | 1797658233174753280 |
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| author | António A. R. Camarão Olivia Luise Gern Felix Stegmann Felix Mulenge Bibiana Costa Babak Saremi Klaus Jung Bernd Lepenies Ulrich Kalinke Imke Steffen |
| author_facet | António A. R. Camarão Olivia Luise Gern Felix Stegmann Felix Mulenge Bibiana Costa Babak Saremi Klaus Jung Bernd Lepenies Ulrich Kalinke Imke Steffen |
| author_sort | António A. R. Camarão |
| collection | DOAJ |
| description | ABSTRACT The flavivirus non-structural protein 1 (NS1) is secreted from infected cells into the circulation and the serum levels correlate with disease severity. The effect of secreted NS1 (sNS1) on non-infected mammalian immune cells is largely unknown. Here, we expressed recombinant sNS1 proteins of tick-borne encephalitis virus (TBEV) and West Nile virus (WNV) and investigated their effects on dendritic cell (DC) effector functions. Murine bone marrow-derived DCs (BMDCs) showed reduced surface expression of co-stimulatory molecules and decreased release of pro-inflammatory cytokines when treated with sNS1 of TBEV or WNV prior to poly(I:C) stimulation. Transcriptional profiles of BMDCs that were sNS1-exposed prior to poly(I:C) stimulation showed two gene clusters that were downregulated by TBEV or WNV sNS1 and that were associated with innate and adaptive immune responses. Functionally, both sNS1 proteins modulated the capacity for BMDCs to induce specific T-cell responses as indicated by reduced IFN-γ levels in both CD4+ and CD8+ T cells after BMDC co-cultivation. In human monocyte-derived DCs, poly(I:C)-induced upregulation of co-stimulatory molecules and cytokine responses were even more strongly impaired by TBEV sNS1 or WNV sNS1 pretreatment than in the murine system. Our findings indicate that exogenous flaviviral sNS1 proteins interfere with DC-mediated stimulation of T cells, which is crucial for the initiation of cell-mediated adaptive immune responses in human flavivirus infections. Collectively, our data determine soluble flaviviral NS1 as a virulence factor responsible for a dampened immune response to flavivirus infections. IMPORTANCE The effective initiation of protective host immune responses controls the outcome of infection, and dysfunctional T-cell responses have previously been associated with symptomatic human flavivirus infections. We demonstrate that secreted flavivirus NS1 proteins modulate innate immune responses of uninfected bystander cells. In particular, sNS1 markedly reduced the capacity of dendritic cells to stimulate T-cell responses upon activation. Hence, by modulating cellular host responses that are required for effective antigen presentation and initiation of adaptive immunity, sNS1 proteins may contribute to severe outcomes of flavivirus disease. |
| first_indexed | 2024-03-11T17:56:16Z |
| format | Article |
| id | doaj.art-8b7b31e7272940889aff0ab0bf7b5f22 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-03-11T17:56:16Z |
| publishDate | 2023-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-8b7b31e7272940889aff0ab0bf7b5f222023-10-17T13:04:35ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-10-0111510.1128/spectrum.02192-23Secreted NS1 proteins of tick-borne encephalitis virus and West Nile virus block dendritic cell activation and effector functionsAntónio A. R. Camarão0Olivia Luise Gern1Felix Stegmann2Felix Mulenge3Bibiana Costa4Babak Saremi5Klaus Jung6Bernd Lepenies7Ulrich Kalinke8Imke Steffen9Institute of Biochemistry, University of Veterinary Medicine Hannover , Hannover, GermanyInstitute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School , Hannover, GermanyResearch Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover , Hannover, GermanyInstitute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School , Hannover, GermanyInstitute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School , Hannover, GermanyInstitute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover , Hannover, GermanyInstitute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover , Hannover, GermanyResearch Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover , Hannover, GermanyInstitute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School , Hannover, GermanyInstitute of Biochemistry, University of Veterinary Medicine Hannover , Hannover, GermanyABSTRACT The flavivirus non-structural protein 1 (NS1) is secreted from infected cells into the circulation and the serum levels correlate with disease severity. The effect of secreted NS1 (sNS1) on non-infected mammalian immune cells is largely unknown. Here, we expressed recombinant sNS1 proteins of tick-borne encephalitis virus (TBEV) and West Nile virus (WNV) and investigated their effects on dendritic cell (DC) effector functions. Murine bone marrow-derived DCs (BMDCs) showed reduced surface expression of co-stimulatory molecules and decreased release of pro-inflammatory cytokines when treated with sNS1 of TBEV or WNV prior to poly(I:C) stimulation. Transcriptional profiles of BMDCs that were sNS1-exposed prior to poly(I:C) stimulation showed two gene clusters that were downregulated by TBEV or WNV sNS1 and that were associated with innate and adaptive immune responses. Functionally, both sNS1 proteins modulated the capacity for BMDCs to induce specific T-cell responses as indicated by reduced IFN-γ levels in both CD4+ and CD8+ T cells after BMDC co-cultivation. In human monocyte-derived DCs, poly(I:C)-induced upregulation of co-stimulatory molecules and cytokine responses were even more strongly impaired by TBEV sNS1 or WNV sNS1 pretreatment than in the murine system. Our findings indicate that exogenous flaviviral sNS1 proteins interfere with DC-mediated stimulation of T cells, which is crucial for the initiation of cell-mediated adaptive immune responses in human flavivirus infections. Collectively, our data determine soluble flaviviral NS1 as a virulence factor responsible for a dampened immune response to flavivirus infections. IMPORTANCE The effective initiation of protective host immune responses controls the outcome of infection, and dysfunctional T-cell responses have previously been associated with symptomatic human flavivirus infections. We demonstrate that secreted flavivirus NS1 proteins modulate innate immune responses of uninfected bystander cells. In particular, sNS1 markedly reduced the capacity of dendritic cells to stimulate T-cell responses upon activation. Hence, by modulating cellular host responses that are required for effective antigen presentation and initiation of adaptive immunity, sNS1 proteins may contribute to severe outcomes of flavivirus disease.https://journals.asm.org/doi/10.1128/spectrum.02192-23flavivirusnon-structural protein 1tick-borne encephalitis virusWest Nile virusdendritic cellsinnate immunity |
| spellingShingle | António A. R. Camarão Olivia Luise Gern Felix Stegmann Felix Mulenge Bibiana Costa Babak Saremi Klaus Jung Bernd Lepenies Ulrich Kalinke Imke Steffen Secreted NS1 proteins of tick-borne encephalitis virus and West Nile virus block dendritic cell activation and effector functions Microbiology Spectrum flavivirus non-structural protein 1 tick-borne encephalitis virus West Nile virus dendritic cells innate immunity |
| title | Secreted NS1 proteins of tick-borne encephalitis virus and West Nile virus block dendritic cell activation and effector functions |
| title_full | Secreted NS1 proteins of tick-borne encephalitis virus and West Nile virus block dendritic cell activation and effector functions |
| title_fullStr | Secreted NS1 proteins of tick-borne encephalitis virus and West Nile virus block dendritic cell activation and effector functions |
| title_full_unstemmed | Secreted NS1 proteins of tick-borne encephalitis virus and West Nile virus block dendritic cell activation and effector functions |
| title_short | Secreted NS1 proteins of tick-borne encephalitis virus and West Nile virus block dendritic cell activation and effector functions |
| title_sort | secreted ns1 proteins of tick borne encephalitis virus and west nile virus block dendritic cell activation and effector functions |
| topic | flavivirus non-structural protein 1 tick-borne encephalitis virus West Nile virus dendritic cells innate immunity |
| url | https://journals.asm.org/doi/10.1128/spectrum.02192-23 |
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