Rift Valley fever virus 78kDa envelope protein attenuates virus replication in macrophage-derived cell lines and viral virulence in mice
Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus with a wide host range including ruminants and humans. RVFV outbreaks have had devastating effects on public health and the livestock industry in African countries. However, there is no approved RVFV vaccine for human use in non-endemic c...
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| description | Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus with a wide host range including ruminants and humans. RVFV outbreaks have had devastating effects on public health and the livestock industry in African countries. However, there is no approved RVFV vaccine for human use in non-endemic countries and no FDA-approved antiviral drug for RVFV treatment. The RVFV 78kDa protein (P78), which is a membrane glycoprotein, plays a role in virus dissemination in the mosquito host, but its biological role in mammalian hosts remains unknown. We generated an attenuated RVFV MP-12 strain-derived P78-High virus and a virulent ZH501 strain-derived ZH501-P78-High virus, both of which expressed a higher level of P78 and carried higher levels of P78 in the virion compared to their parental viruses. We also generated another MP-12-derived mutant virus (P78-KO virus) that does not express P78. MP-12 and P78-KO virus replicated to similar levels in fibroblast cell lines and Huh7 cells, while P78-High virus replicated better than MP-12 in Vero E6 cells, fibroblast cell lines, and Huh7 cells. Notably, P78-High virus and P78-KO virus replicated less efficiently and more efficiently, respectively, than MP-12 in macrophage cell lines. ZH501-P78-High virus also replicated poorly in macrophage cell lines. Our data further suggest that inefficient binding of P78-High virus to the cells led to inefficient virus internalization, low virus infectivity and reduced virus replication in a macrophage cell line. P78-High virus and P78-KO virus showed lower and higher virulence than MP-12, respectively, in young mice. ZH501-P78-High virus also exhibited lower virulence than ZH501 in mice. These data suggest that high levels of P78 expression attenuate RVFV virulence by preventing efficient virus replication in macrophages. Genetic alteration leading to increased P78 expression may serve as a novel strategy for the attenuation of RVFV virulence and generation of safe RVFV vaccines. |
| doi_str_mv | 10.1371/journal.pntd.0009785 |
| format | Article |
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RVFV outbreaks have had devastating effects on public health and the livestock industry in African countries. However, there is no approved RVFV vaccine for human use in non-endemic countries and no FDA-approved antiviral drug for RVFV treatment. The RVFV 78kDa protein (P78), which is a membrane glycoprotein, plays a role in virus dissemination in the mosquito host, but its biological role in mammalian hosts remains unknown. We generated an attenuated RVFV MP-12 strain-derived P78-High virus and a virulent ZH501 strain-derived ZH501-P78-High virus, both of which expressed a higher level of P78 and carried higher levels of P78 in the virion compared to their parental viruses. We also generated another MP-12-derived mutant virus (P78-KO virus) that does not express P78. MP-12 and P78-KO virus replicated to similar levels in fibroblast cell lines and Huh7 cells, while P78-High virus replicated better than MP-12 in Vero E6 cells, fibroblast cell lines, and Huh7 cells. Notably, P78-High virus and P78-KO virus replicated less efficiently and more efficiently, respectively, than MP-12 in macrophage cell lines. ZH501-P78-High virus also replicated poorly in macrophage cell lines. Our data further suggest that inefficient binding of P78-High virus to the cells led to inefficient virus internalization, low virus infectivity and reduced virus replication in a macrophage cell line. P78-High virus and P78-KO virus showed lower and higher virulence than MP-12, respectively, in young mice. ZH501-P78-High virus also exhibited lower virulence than ZH501 in mice. These data suggest that high levels of P78 expression attenuate RVFV virulence by preventing efficient virus replication in macrophages. Genetic alteration leading to increased P78 expression may serve as a novel strategy for the attenuation of RVFV virulence and generation of safe RVFV vaccines.</description><identifier>ISSN: 1935-2735</identifier><identifier>ISSN: 1935-2727</identifier><identifier>EISSN: 1935-2735</identifier><identifier>DOI: 10.1371/journal.pntd.0009785</identifier><identifier>PMID: 34516560</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino acids ; Animals ; Antiviral agents ; Aquatic insects ; Attenuation ; Biology and Life Sciences ; Bunyaviruses ; Cell lines ; Cells ; Coccidioidomycosis ; Countries ; Disease control ; Drug therapy ; Fever ; Genetic aspects ; Glycoproteins ; Host range ; Infectivity ; Internalization ; Laboratory animals ; Levels ; Livestock ; Livestock industry ; Macrophages ; Macrophages - virology ; Mammals ; Medicine and health sciences ; Membrane proteins ; Mice ; Microbiological strains ; Mortality ; Mosquitoes ; Physical Sciences ; Physiological aspects ; Prevention ; Proteins ; Public health ; Replication ; Research and Analysis Methods ; Rift Valley fever ; Rift Valley Fever - virology ; Rift Valley fever virus - pathogenicity ; Rift Valley fever virus - physiology ; RNA polymerase ; Strain ; Tropical diseases ; Vaccines ; Vector-borne diseases ; Viral diseases ; Viral envelope proteins ; Viral Envelope Proteins - genetics ; Viral Envelope Proteins - metabolism ; Viral envelopes ; Viral vaccines ; Virions ; Virulence ; Virulence (Microbiology) ; Virus Replication - physiology ; Virus research ; Viruses</subject><ispartof>PLoS neglected tropical diseases, 2021-09, Vol.15 (9), p.e0009785-e0009785</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Terasaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Terasaki et al 2021 Terasaki et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c624t-12cea2b605b937c5428ff3171653eaa8947497e1ceb65acfc4b2aab13f86e1563</citedby><cites>FETCH-LOGICAL-c624t-12cea2b605b937c5428ff3171653eaa8947497e1ceb65acfc4b2aab13f86e1563</cites><orcidid>0000-0001-6997-8689 ; 0000-0002-7831-1576 ; 0000-0001-8413-8960 ; 0000-0001-9824-1846</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460012/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460012/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34516560$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Klingström, Jonas</contributor><creatorcontrib>Terasaki, Kaori</creatorcontrib><creatorcontrib>Kalveram, Birte</creatorcontrib><creatorcontrib>Johnson, Kendra N</creatorcontrib><creatorcontrib>Juelich, Terry</creatorcontrib><creatorcontrib>Smith, Jennifer K</creatorcontrib><creatorcontrib>Zhang, Lihong</creatorcontrib><creatorcontrib>Freiberg, Alexander N</creatorcontrib><creatorcontrib>Makino, Shinji</creatorcontrib><title>Rift Valley fever virus 78kDa envelope protein attenuates virus replication in macrophage-derived cell lines and viral virulence in mice</title><title>PLoS neglected tropical diseases</title><addtitle>PLoS Negl Trop Dis</addtitle><description>Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus with a wide host range including ruminants and humans. RVFV outbreaks have had devastating effects on public health and the livestock industry in African countries. However, there is no approved RVFV vaccine for human use in non-endemic countries and no FDA-approved antiviral drug for RVFV treatment. The RVFV 78kDa protein (P78), which is a membrane glycoprotein, plays a role in virus dissemination in the mosquito host, but its biological role in mammalian hosts remains unknown. We generated an attenuated RVFV MP-12 strain-derived P78-High virus and a virulent ZH501 strain-derived ZH501-P78-High virus, both of which expressed a higher level of P78 and carried higher levels of P78 in the virion compared to their parental viruses. We also generated another MP-12-derived mutant virus (P78-KO virus) that does not express P78. MP-12 and P78-KO virus replicated to similar levels in fibroblast cell lines and Huh7 cells, while P78-High virus replicated better than MP-12 in Vero E6 cells, fibroblast cell lines, and Huh7 cells. Notably, P78-High virus and P78-KO virus replicated less efficiently and more efficiently, respectively, than MP-12 in macrophage cell lines. ZH501-P78-High virus also replicated poorly in macrophage cell lines. Our data further suggest that inefficient binding of P78-High virus to the cells led to inefficient virus internalization, low virus infectivity and reduced virus replication in a macrophage cell line. P78-High virus and P78-KO virus showed lower and higher virulence than MP-12, respectively, in young mice. ZH501-P78-High virus also exhibited lower virulence than ZH501 in mice. These data suggest that high levels of P78 expression attenuate RVFV virulence by preventing efficient virus replication in macrophages. Genetic alteration leading to increased P78 expression may serve as a novel strategy for the attenuation of RVFV virulence and generation of safe RVFV vaccines.</description><subject>Amino acids</subject><subject>Animals</subject><subject>Antiviral agents</subject><subject>Aquatic insects</subject><subject>Attenuation</subject><subject>Biology and Life Sciences</subject><subject>Bunyaviruses</subject><subject>Cell lines</subject><subject>Cells</subject><subject>Coccidioidomycosis</subject><subject>Countries</subject><subject>Disease control</subject><subject>Drug therapy</subject><subject>Fever</subject><subject>Genetic aspects</subject><subject>Glycoproteins</subject><subject>Host range</subject><subject>Infectivity</subject><subject>Internalization</subject><subject>Laboratory animals</subject><subject>Levels</subject><subject>Livestock</subject><subject>Livestock industry</subject><subject>Macrophages</subject><subject>Macrophages - virology</subject><subject>Mammals</subject><subject>Medicine and health sciences</subject><subject>Membrane proteins</subject><subject>Mice</subject><subject>Microbiological strains</subject><subject>Mortality</subject><subject>Mosquitoes</subject><subject>Physical Sciences</subject><subject>Physiological aspects</subject><subject>Prevention</subject><subject>Proteins</subject><subject>Public health</subject><subject>Replication</subject><subject>Research and Analysis Methods</subject><subject>Rift Valley fever</subject><subject>Rift Valley Fever - virology</subject><subject>Rift Valley fever virus - pathogenicity</subject><subject>Rift Valley fever virus - physiology</subject><subject>RNA polymerase</subject><subject>Strain</subject><subject>Tropical diseases</subject><subject>Vaccines</subject><subject>Vector-borne diseases</subject><subject>Viral diseases</subject><subject>Viral envelope proteins</subject><subject>Viral Envelope Proteins - genetics</subject><subject>Viral Envelope Proteins - metabolism</subject><subject>Viral envelopes</subject><subject>Viral vaccines</subject><subject>Virions</subject><subject>Virulence</subject><subject>Virulence (Microbiology)</subject><subject>Virus Replication - physiology</subject><subject>Virus research</subject><subject>Viruses</subject><issn>1935-2735</issn><issn>1935-2727</issn><issn>1935-2735</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUl2L1DAULaK46-o_EC0I4suMSdM07YuwrF8LC4Kor-E2vZ3JmElqkg7sP_Bnm850lxlZEkhIzjk39-Rk2UtKlpQJ-n7jRm_BLAcbuyUhpBE1f5Sd04bxRSEYf3y0P8uehbAhhDe8pk-zM1ZyWvGKnGd_v-s-5r_AGLzNe9yhz3fajyEX9e-PkKPdoXED5oN3EbXNIUa0I0QMM87jYLSCqJ3N0_0WlHfDGla46NDrHXa5QmNyo22igO0mGpg92aBVuCdphc-zJz2YgC_m9SL7-fnTj6uvi5tvX66vLm8WqirKuKCFQijaivC2YULxsqj7nlGR2mEIUDelKBuBVGFbcVC9KtsCoKWsryukvGIX2euD7mBckLOJQRa8TrNsiiYhrg-IzsFGDl5vwd9KB1ruD5xfSfBRK4NSCA59pUjdEl4SyptGdB1vkNOaUdoWSevDXG1st9gptDF1fyJ6emP1Wq7cTtZlRQidBN7NAt79GTFEudVhchQsunF6tyg4Y4KUCfrmP-jD3c2oFaQGtO1dqqsmUXlZCdHUnFeTS8sHUGl0mD7LWex1Oj8hvD0irBFMXAdnxikX4RRYHoApJyF47O_NoEROwb57tZyCLedgJ9qrYyPvSXdJZv8AuHD2UA</recordid><startdate>20210901</startdate><enddate>20210901</enddate><creator>Terasaki, Kaori</creator><creator>Kalveram, Birte</creator><creator>Johnson, Kendra N</creator><creator>Juelich, Terry</creator><creator>Smith, Jennifer K</creator><creator>Zhang, Lihong</creator><creator>Freiberg, Alexander N</creator><creator>Makino, Shinji</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7SS</scope><scope>7T2</scope><scope>7T7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8C1</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>F1W</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>H95</scope><scope>H97</scope><scope>K9.</scope><scope>L.G</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-6997-8689</orcidid><orcidid>https://orcid.org/0000-0002-7831-1576</orcidid><orcidid>https://orcid.org/0000-0001-8413-8960</orcidid><orcidid>https://orcid.org/0000-0001-9824-1846</orcidid></search><sort><creationdate>20210901</creationdate><title>Rift Valley fever virus 78kDa envelope protein attenuates virus replication in macrophage-derived cell lines and viral virulence in mice</title><author>Terasaki, Kaori ; Kalveram, Birte ; Johnson, Kendra N ; Juelich, Terry ; Smith, Jennifer K ; Zhang, Lihong ; Freiberg, Alexander N ; Makino, Shinji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c624t-12cea2b605b937c5428ff3171653eaa8947497e1ceb65acfc4b2aab13f86e1563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Amino acids</topic><topic>Animals</topic><topic>Antiviral agents</topic><topic>Aquatic insects</topic><topic>Attenuation</topic><topic>Biology and Life Sciences</topic><topic>Bunyaviruses</topic><topic>Cell lines</topic><topic>Cells</topic><topic>Coccidioidomycosis</topic><topic>Countries</topic><topic>Disease control</topic><topic>Drug therapy</topic><topic>Fever</topic><topic>Genetic aspects</topic><topic>Glycoproteins</topic><topic>Host range</topic><topic>Infectivity</topic><topic>Internalization</topic><topic>Laboratory animals</topic><topic>Levels</topic><topic>Livestock</topic><topic>Livestock industry</topic><topic>Macrophages</topic><topic>Macrophages - 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RVFV outbreaks have had devastating effects on public health and the livestock industry in African countries. However, there is no approved RVFV vaccine for human use in non-endemic countries and no FDA-approved antiviral drug for RVFV treatment. The RVFV 78kDa protein (P78), which is a membrane glycoprotein, plays a role in virus dissemination in the mosquito host, but its biological role in mammalian hosts remains unknown. We generated an attenuated RVFV MP-12 strain-derived P78-High virus and a virulent ZH501 strain-derived ZH501-P78-High virus, both of which expressed a higher level of P78 and carried higher levels of P78 in the virion compared to their parental viruses. We also generated another MP-12-derived mutant virus (P78-KO virus) that does not express P78. MP-12 and P78-KO virus replicated to similar levels in fibroblast cell lines and Huh7 cells, while P78-High virus replicated better than MP-12 in Vero E6 cells, fibroblast cell lines, and Huh7 cells. Notably, P78-High virus and P78-KO virus replicated less efficiently and more efficiently, respectively, than MP-12 in macrophage cell lines. ZH501-P78-High virus also replicated poorly in macrophage cell lines. Our data further suggest that inefficient binding of P78-High virus to the cells led to inefficient virus internalization, low virus infectivity and reduced virus replication in a macrophage cell line. P78-High virus and P78-KO virus showed lower and higher virulence than MP-12, respectively, in young mice. ZH501-P78-High virus also exhibited lower virulence than ZH501 in mice. These data suggest that high levels of P78 expression attenuate RVFV virulence by preventing efficient virus replication in macrophages. Genetic alteration leading to increased P78 expression may serve as a novel strategy for the attenuation of RVFV virulence and generation of safe RVFV vaccines.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>34516560</pmid><doi>10.1371/journal.pntd.0009785</doi><orcidid>https://orcid.org/0000-0001-6997-8689</orcidid><orcidid>https://orcid.org/0000-0002-7831-1576</orcidid><orcidid>https://orcid.org/0000-0001-8413-8960</orcidid><orcidid>https://orcid.org/0000-0001-9824-1846</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_2582584929 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; PubMed Central Open Access |
| subjects | Amino acids Animals Antiviral agents Aquatic insects Attenuation Biology and Life Sciences Bunyaviruses Cell lines Cells Coccidioidomycosis Countries Disease control Drug therapy Fever Genetic aspects Glycoproteins Host range Infectivity Internalization Laboratory animals Levels Livestock Livestock industry Macrophages Macrophages - virology Mammals Medicine and health sciences Membrane proteins Mice Microbiological strains Mortality Mosquitoes Physical Sciences Physiological aspects Prevention Proteins Public health Replication Research and Analysis Methods Rift Valley fever Rift Valley Fever - virology Rift Valley fever virus - pathogenicity Rift Valley fever virus - physiology RNA polymerase Strain Tropical diseases Vaccines Vector-borne diseases Viral diseases Viral envelope proteins Viral Envelope Proteins - genetics Viral Envelope Proteins - metabolism Viral envelopes Viral vaccines Virions Virulence Virulence (Microbiology) Virus Replication - physiology Virus research Viruses |
| title | Rift Valley fever virus 78kDa envelope protein attenuates virus replication in macrophage-derived cell lines and viral virulence in mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T18%3A39%3A22IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Rift%20Valley%20fever%20virus%2078kDa%20envelope%20protein%20attenuates%20virus%20replication%20in%20macrophage-derived%20cell%20lines%20and%20viral%20virulence%20in%20mice&rft.jtitle=PLoS%20neglected%20tropical%20diseases&rft.au=Terasaki,%20Kaori&rft.date=2021-09-01&rft.volume=15&rft.issue=9&rft.spage=e0009785&rft.epage=e0009785&rft.pages=e0009785-e0009785&rft.issn=1935-2735&rft.eissn=1935-2735&rft_id=info:doi/10.1371/journal.pntd.0009785&rft_dat=%3Cgale_plos_%3EA677985566%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2582584929&rft_id=info:pmid/34516560&rft_galeid=A677985566&rft_doaj_id=oai_doaj_org_article_775af6c08b054015997dd59e518311b2&rfr_iscdi=true |