A single mutation in the E2 glycoprotein of hepatitis C virus broadens the claudin specificity for its infection
Abstract Entry of the hepatitis C virus (HCV) into host cells is a multistep process mediated by several host factors, including a tight junction protein claudin-1 (CLDN1). We repeatedly passaged HCV-JFH1-tau, an HCV substrain with higher infectivity, on Huh7.5.1-8 cells. A multi-passaged HCV-JFH1-t...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-11-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-23824-3 |
| _version_ | 1811210968870420480 |
|---|---|
| author | Yoshitaka Shirasago Hidesuke Fukazawa Shotaro Nagase Yoshimi Shimizu Tomoharu Mizukami Takaji Wakita Tetsuro Suzuki Hideki Tani Masuo Kondoh Takuya Kuroda Satoshi Yasuda Yoji Sato Kentaro Hanada Masayoshi Fukasawa |
| author_facet | Yoshitaka Shirasago Hidesuke Fukazawa Shotaro Nagase Yoshimi Shimizu Tomoharu Mizukami Takaji Wakita Tetsuro Suzuki Hideki Tani Masuo Kondoh Takuya Kuroda Satoshi Yasuda Yoji Sato Kentaro Hanada Masayoshi Fukasawa |
| author_sort | Yoshitaka Shirasago |
| collection | DOAJ |
| description | Abstract Entry of the hepatitis C virus (HCV) into host cells is a multistep process mediated by several host factors, including a tight junction protein claudin-1 (CLDN1). We repeatedly passaged HCV-JFH1-tau, an HCV substrain with higher infectivity, on Huh7.5.1-8 cells. A multi-passaged HCV-JFH1-tau lot was infectious to CLDN1-defective S7-A cells, non-permissive to original HCV-JFH1-tau infection. We identified a single mutation, M706L, in the E2 glycoprotein of the HCV-JFH1-tau lot as an essential mutation for infectivity to S7-A cells. The pseudovirus JFH1/M706L mutant could not infect human embryonic kidney 293 T (HEK293T) cells lacking CLDN family but infected HEK293T cells expressing CLDN1, CLDN6, or CLDN9. Thus, this mutant virus could utilize CLDN1, and other CLDN6 and CLDN9, making HCV possible to infect cells other than hepatocytes. iPS cells, one of the stem cells, do not express CLDN1 but express CLDN6 and other host factors required for HCV infection. We confirmed that the HCV-JFH1-tau-derived mutant with an M706L mutation infected iPS cells in a CLDN6-dependent manner. These results demonstrated that a missense mutation in E2 could broaden the CLDN member specificity for HCV infection. HCV may change its receptor requirement through a single amino acid mutation and infect non-hepatic cells. |
| first_indexed | 2024-04-12T05:04:54Z |
| format | Article |
| id | doaj.art-6ab2437809074c90b54dbaa6bfc1c9e2 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T05:04:54Z |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-6ab2437809074c90b54dbaa6bfc1c9e22022-12-22T03:46:54ZengNature PortfolioScientific Reports2045-23222022-11-0112111210.1038/s41598-022-23824-3A single mutation in the E2 glycoprotein of hepatitis C virus broadens the claudin specificity for its infectionYoshitaka Shirasago0Hidesuke Fukazawa1Shotaro Nagase2Yoshimi Shimizu3Tomoharu Mizukami4Takaji Wakita5Tetsuro Suzuki6Hideki Tani7Masuo Kondoh8Takuya Kuroda9Satoshi Yasuda10Yoji Sato11Kentaro Hanada12Masayoshi Fukasawa13Department of Biochemistry and Cell Biology, National Institute of Infectious DiseasesDepartment of Quality Assurance, Radiation Safety, and Information System, National Institute of Infectious DiseasesGraduate School of Pharmaceutical Sciences, Osaka UniversityDepartment of Biochemistry and Cell Biology, National Institute of Infectious DiseasesDepartment of Biochemistry and Cell Biology, National Institute of Infectious DiseasesNational Institute of Infectious DiseasesDepartment of Infectious Diseases, Hamamatsu University School of MedicineDepartment of Virology, Toyama Institute of HealthGraduate School of Pharmaceutical Sciences, Osaka UniversityDivision of Cell-Based Therapeutic Products, National Institute of Health SciencesDivision of Cell-Based Therapeutic Products, National Institute of Health SciencesDivision of Cell-Based Therapeutic Products, National Institute of Health SciencesDepartment of Biochemistry and Cell Biology, National Institute of Infectious DiseasesDepartment of Biochemistry and Cell Biology, National Institute of Infectious DiseasesAbstract Entry of the hepatitis C virus (HCV) into host cells is a multistep process mediated by several host factors, including a tight junction protein claudin-1 (CLDN1). We repeatedly passaged HCV-JFH1-tau, an HCV substrain with higher infectivity, on Huh7.5.1-8 cells. A multi-passaged HCV-JFH1-tau lot was infectious to CLDN1-defective S7-A cells, non-permissive to original HCV-JFH1-tau infection. We identified a single mutation, M706L, in the E2 glycoprotein of the HCV-JFH1-tau lot as an essential mutation for infectivity to S7-A cells. The pseudovirus JFH1/M706L mutant could not infect human embryonic kidney 293 T (HEK293T) cells lacking CLDN family but infected HEK293T cells expressing CLDN1, CLDN6, or CLDN9. Thus, this mutant virus could utilize CLDN1, and other CLDN6 and CLDN9, making HCV possible to infect cells other than hepatocytes. iPS cells, one of the stem cells, do not express CLDN1 but express CLDN6 and other host factors required for HCV infection. We confirmed that the HCV-JFH1-tau-derived mutant with an M706L mutation infected iPS cells in a CLDN6-dependent manner. These results demonstrated that a missense mutation in E2 could broaden the CLDN member specificity for HCV infection. HCV may change its receptor requirement through a single amino acid mutation and infect non-hepatic cells.https://doi.org/10.1038/s41598-022-23824-3 |
| spellingShingle | Yoshitaka Shirasago Hidesuke Fukazawa Shotaro Nagase Yoshimi Shimizu Tomoharu Mizukami Takaji Wakita Tetsuro Suzuki Hideki Tani Masuo Kondoh Takuya Kuroda Satoshi Yasuda Yoji Sato Kentaro Hanada Masayoshi Fukasawa A single mutation in the E2 glycoprotein of hepatitis C virus broadens the claudin specificity for its infection Scientific Reports |
| title | A single mutation in the E2 glycoprotein of hepatitis C virus broadens the claudin specificity for its infection |
| title_full | A single mutation in the E2 glycoprotein of hepatitis C virus broadens the claudin specificity for its infection |
| title_fullStr | A single mutation in the E2 glycoprotein of hepatitis C virus broadens the claudin specificity for its infection |
| title_full_unstemmed | A single mutation in the E2 glycoprotein of hepatitis C virus broadens the claudin specificity for its infection |
| title_short | A single mutation in the E2 glycoprotein of hepatitis C virus broadens the claudin specificity for its infection |
| title_sort | single mutation in the e2 glycoprotein of hepatitis c virus broadens the claudin specificity for its infection |
| url | https://doi.org/10.1038/s41598-022-23824-3 |
| work_keys_str_mv | AT yoshitakashirasago asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT hidesukefukazawa asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT shotaronagase asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT yoshimishimizu asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT tomoharumizukami asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT takajiwakita asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT tetsurosuzuki asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT hidekitani asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT masuokondoh asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT takuyakuroda asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT satoshiyasuda asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT yojisato asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT kentarohanada asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT masayoshifukasawa asinglemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT yoshitakashirasago singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT hidesukefukazawa singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT shotaronagase singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT yoshimishimizu singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT tomoharumizukami singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT takajiwakita singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT tetsurosuzuki singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT hidekitani singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT masuokondoh singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT takuyakuroda singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT satoshiyasuda singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT yojisato singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT kentarohanada singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection AT masayoshifukasawa singlemutationinthee2glycoproteinofhepatitiscvirusbroadenstheclaudinspecificityforitsinfection |