Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses
Influenza A virus (IAV) is a significant human pathogen that causes seasonal epidemics. Although various types of vaccines are available, IAVs still circulate among human populations, possibly due to their ability to circumvent host immune responses. IAV expresses two host shutoff proteins, PA-X and...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-06-01
|
| Series: | Vaccines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-393X/9/6/629 |
| _version_ | 1827690178201780224 |
|---|---|
| author | Megan M. Dunagan Kala Hardy Toru Takimoto |
| author_facet | Megan M. Dunagan Kala Hardy Toru Takimoto |
| author_sort | Megan M. Dunagan |
| collection | DOAJ |
| description | Influenza A virus (IAV) is a significant human pathogen that causes seasonal epidemics. Although various types of vaccines are available, IAVs still circulate among human populations, possibly due to their ability to circumvent host immune responses. IAV expresses two host shutoff proteins, PA-X and NS1, which antagonize the host innate immune response. By transcriptomic analysis, we previously showed that PA-X is a major contributor for general shutoff, while shutoff active NS1 specifically inhibits the expression of host cytokines, MHC molecules, and genes involved in innate immunity in cultured human cells. So far, the impact of these shutoff proteins in the acquired immune response in vivo has not been determined in detail. In this study, we analyzed the effects of PA-X and NS1 shutoff activities on immune response using recombinant influenza A/California/04/2009 viruses containing mutations affecting the expression of shutoff active PA-X and NS1 in a mouse model. Our data indicate that the virus without shutoff activities induced the strongest T and B cell responses. Both PA-X and NS1 reduced host immune responses, but shutoff active NS1 most effectively suppressed lymphocyte migration to the lungs, antibody production, and the generation of IAV specific CD4<sup>+</sup> and CD8<sup>+</sup> T cells. NS1 also prevented the generation of protective immunity against a heterologous virus challenge. These data indicate that shutoff active NS1 plays a major role in suppressing host immune responses against IAV infection. |
| first_indexed | 2024-03-10T10:33:44Z |
| format | Article |
| id | doaj.art-ee740d210af441e4b228e77b33571dfd |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-03-10T10:33:44Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-ee740d210af441e4b228e77b33571dfd2023-11-21T23:29:59ZengMDPI AGVaccines2076-393X2021-06-019662910.3390/vaccines9060629Impact of Influenza A Virus Shutoff Proteins on Host Immune ResponsesMegan M. Dunagan0Kala Hardy1Toru Takimoto2Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USADepartment of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USADepartment of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USAInfluenza A virus (IAV) is a significant human pathogen that causes seasonal epidemics. Although various types of vaccines are available, IAVs still circulate among human populations, possibly due to their ability to circumvent host immune responses. IAV expresses two host shutoff proteins, PA-X and NS1, which antagonize the host innate immune response. By transcriptomic analysis, we previously showed that PA-X is a major contributor for general shutoff, while shutoff active NS1 specifically inhibits the expression of host cytokines, MHC molecules, and genes involved in innate immunity in cultured human cells. So far, the impact of these shutoff proteins in the acquired immune response in vivo has not been determined in detail. In this study, we analyzed the effects of PA-X and NS1 shutoff activities on immune response using recombinant influenza A/California/04/2009 viruses containing mutations affecting the expression of shutoff active PA-X and NS1 in a mouse model. Our data indicate that the virus without shutoff activities induced the strongest T and B cell responses. Both PA-X and NS1 reduced host immune responses, but shutoff active NS1 most effectively suppressed lymphocyte migration to the lungs, antibody production, and the generation of IAV specific CD4<sup>+</sup> and CD8<sup>+</sup> T cells. NS1 also prevented the generation of protective immunity against a heterologous virus challenge. These data indicate that shutoff active NS1 plays a major role in suppressing host immune responses against IAV infection.https://www.mdpi.com/2076-393X/9/6/629influenza A virushost shutoffNS1PA-X |
| spellingShingle | Megan M. Dunagan Kala Hardy Toru Takimoto Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses Vaccines influenza A virus host shutoff NS1 PA-X |
| title | Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses |
| title_full | Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses |
| title_fullStr | Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses |
| title_full_unstemmed | Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses |
| title_short | Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses |
| title_sort | impact of influenza a virus shutoff proteins on host immune responses |
| topic | influenza A virus host shutoff NS1 PA-X |
| url | https://www.mdpi.com/2076-393X/9/6/629 |
| work_keys_str_mv | AT meganmdunagan impactofinfluenzaavirusshutoffproteinsonhostimmuneresponses AT kalahardy impactofinfluenzaavirusshutoffproteinsonhostimmuneresponses AT torutakimoto impactofinfluenzaavirusshutoffproteinsonhostimmuneresponses |