In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age.
Despite limited genomic diversity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a wide range of clinical manifestations in different patient populations. The mechanisms behind these host differences are still unclear. Here, we examined host response gene expression across i...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-09-01
|
| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3000849 |
| _version_ | 1830199424704315392 |
|---|---|
| author | Nicole A P Lieberman Vikas Peddu Hong Xie Lasata Shrestha Meei-Li Huang Megan C Mears Maria N Cajimat Dennis A Bente Pei-Yong Shi Francesca Bovier Pavitra Roychoudhury Keith R Jerome Anne Moscona Matteo Porotto Alexander L Greninger |
| author_facet | Nicole A P Lieberman Vikas Peddu Hong Xie Lasata Shrestha Meei-Li Huang Megan C Mears Maria N Cajimat Dennis A Bente Pei-Yong Shi Francesca Bovier Pavitra Roychoudhury Keith R Jerome Anne Moscona Matteo Porotto Alexander L Greninger |
| author_sort | Nicole A P Lieberman |
| collection | DOAJ |
| description | Despite limited genomic diversity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a wide range of clinical manifestations in different patient populations. The mechanisms behind these host differences are still unclear. Here, we examined host response gene expression across infection status, viral load, age, and sex among shotgun RNA sequencing profiles of nasopharyngeal (NP) swabs from 430 individuals with PCR-confirmed SARS-CoV-2 and 54 negative controls. SARS-CoV-2 induced a strong antiviral response with up-regulation of antiviral factors such as OAS1-3 and IFIT1-3 and T helper type 1 (Th1) chemokines CXCL9/10/11, as well as a reduction in transcription of ribosomal proteins. SARS-CoV-2 culture in human airway epithelial (HAE) cultures replicated the in vivo antiviral host response 7 days post infection, with no induction of interferon-stimulated genes after 3 days. Patient-matched longitudinal specimens (mean elapsed time = 6.3 days) demonstrated reduction in interferon-induced transcription, recovery of transcription of ribosomal proteins, and initiation of wound healing and humoral immune responses. Expression of interferon-responsive genes, including ACE2, increased as a function of viral load, while transcripts for B cell-specific proteins and neutrophil chemokines were elevated in patients with lower viral load. Older individuals had reduced expression of the Th1 chemokines CXCL9/10/11 and their cognate receptor CXCR3, as well as CD8A and granzyme B, suggesting deficiencies in trafficking and/or function of cytotoxic T cells and natural killer (NK) cells. Relative to females, males had reduced B cell-specific and NK cell-specific transcripts and an increase in inhibitors of nuclear factor kappa-B (NF-κB) signaling, possibly inappropriately throttling antiviral responses. Collectively, our data demonstrate that host responses to SARS-CoV-2 are dependent on viral load and infection time course, with observed differences due to age and sex that may contribute to disease severity. |
| first_indexed | 2024-12-18T02:12:31Z |
| format | Article |
| id | doaj.art-daaebf39e64a4d86833f32bea472d70f |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-18T02:12:31Z |
| publishDate | 2020-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-daaebf39e64a4d86833f32bea472d70f2022-12-21T21:24:27ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852020-09-01189e300084910.1371/journal.pbio.3000849In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age.Nicole A P LiebermanVikas PedduHong XieLasata ShresthaMeei-Li HuangMegan C MearsMaria N CajimatDennis A BentePei-Yong ShiFrancesca BovierPavitra RoychoudhuryKeith R JeromeAnne MosconaMatteo PorottoAlexander L GreningerDespite limited genomic diversity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a wide range of clinical manifestations in different patient populations. The mechanisms behind these host differences are still unclear. Here, we examined host response gene expression across infection status, viral load, age, and sex among shotgun RNA sequencing profiles of nasopharyngeal (NP) swabs from 430 individuals with PCR-confirmed SARS-CoV-2 and 54 negative controls. SARS-CoV-2 induced a strong antiviral response with up-regulation of antiviral factors such as OAS1-3 and IFIT1-3 and T helper type 1 (Th1) chemokines CXCL9/10/11, as well as a reduction in transcription of ribosomal proteins. SARS-CoV-2 culture in human airway epithelial (HAE) cultures replicated the in vivo antiviral host response 7 days post infection, with no induction of interferon-stimulated genes after 3 days. Patient-matched longitudinal specimens (mean elapsed time = 6.3 days) demonstrated reduction in interferon-induced transcription, recovery of transcription of ribosomal proteins, and initiation of wound healing and humoral immune responses. Expression of interferon-responsive genes, including ACE2, increased as a function of viral load, while transcripts for B cell-specific proteins and neutrophil chemokines were elevated in patients with lower viral load. Older individuals had reduced expression of the Th1 chemokines CXCL9/10/11 and their cognate receptor CXCR3, as well as CD8A and granzyme B, suggesting deficiencies in trafficking and/or function of cytotoxic T cells and natural killer (NK) cells. Relative to females, males had reduced B cell-specific and NK cell-specific transcripts and an increase in inhibitors of nuclear factor kappa-B (NF-κB) signaling, possibly inappropriately throttling antiviral responses. Collectively, our data demonstrate that host responses to SARS-CoV-2 are dependent on viral load and infection time course, with observed differences due to age and sex that may contribute to disease severity.https://doi.org/10.1371/journal.pbio.3000849 |
| spellingShingle | Nicole A P Lieberman Vikas Peddu Hong Xie Lasata Shrestha Meei-Li Huang Megan C Mears Maria N Cajimat Dennis A Bente Pei-Yong Shi Francesca Bovier Pavitra Roychoudhury Keith R Jerome Anne Moscona Matteo Porotto Alexander L Greninger In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age. PLoS Biology |
| title | In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age. |
| title_full | In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age. |
| title_fullStr | In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age. |
| title_full_unstemmed | In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age. |
| title_short | In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age. |
| title_sort | in vivo antiviral host transcriptional response to sars cov 2 by viral load sex and age |
| url | https://doi.org/10.1371/journal.pbio.3000849 |
| work_keys_str_mv | AT nicoleaplieberman invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT vikaspeddu invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT hongxie invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT lasatashrestha invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT meeilihuang invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT megancmears invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT mariancajimat invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT dennisabente invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT peiyongshi invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT francescabovier invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT pavitraroychoudhury invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT keithrjerome invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT annemoscona invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT matteoporotto invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage AT alexanderlgreninger invivoantiviralhosttranscriptionalresponsetosarscov2byviralloadsexandage |