CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses.
Exacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the primary target cells of SARS-CoV-2 infection in humans, viral RNA and antigens in activated monocytes and m...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-10-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1010479 |
| _version_ | 1797856362687889408 |
|---|---|
| author | Sallieu Jalloh Judith Olejnik Jacob Berrigan Annuurun Nisa Ellen L Suder Hisashi Akiyama Maohua Lei Sita Ramaswamy Sanjay Tyagi Yuri Bushkin Elke Mühlberger Suryaram Gummuluru |
| author_facet | Sallieu Jalloh Judith Olejnik Jacob Berrigan Annuurun Nisa Ellen L Suder Hisashi Akiyama Maohua Lei Sita Ramaswamy Sanjay Tyagi Yuri Bushkin Elke Mühlberger Suryaram Gummuluru |
| author_sort | Sallieu Jalloh |
| collection | DOAJ |
| description | Exacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the primary target cells of SARS-CoV-2 infection in humans, viral RNA and antigens in activated monocytes and macrophages have been detected in post-mortem samples, and dysfunctional monocytes and macrophages have been hypothesized to contribute to a protracted hyper-inflammatory state in COVID-19 patients. In this study, we demonstrate that CD169, a myeloid cell specific I-type lectin, facilitated ACE2-independent SARS-CoV-2 fusion and entry in macrophages. CD169-mediated SARS-CoV-2 entry in macrophages resulted in expression of viral genomic and subgenomic RNAs with minimal viral protein expression and no infectious viral particle release, suggesting a post-entry restriction of the SARS-CoV-2 replication cycle. Intriguingly this post-entry replication block was alleviated by exogenous ACE2 expression in macrophages. Restricted expression of viral genomic and subgenomic RNA in CD169+ macrophages elicited a pro-inflammatory cytokine expression (TNFα, IL-6 and IL-1β) in a RIG-I, MDA-5 and MAVS-dependent manner, which was suppressed by remdesivir treatment. These findings suggest that de novo expression of SARS-CoV-2 RNA in macrophages contributes to the pro-inflammatory cytokine signature and that blocking CD169-mediated ACE2 independent infection and subsequent activation of macrophages by viral RNA might alleviate COVID-19-associated hyperinflammatory response. |
| first_indexed | 2024-04-09T20:40:12Z |
| format | Article |
| id | doaj.art-85f8d9b4a0a64408996252c3e4b0c0a8 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-09T20:40:12Z |
| publishDate | 2022-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-85f8d9b4a0a64408996252c3e4b0c0a82023-03-30T05:31:08ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742022-10-011810e101047910.1371/journal.ppat.1010479CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses.Sallieu JallohJudith OlejnikJacob BerriganAnnuurun NisaEllen L SuderHisashi AkiyamaMaohua LeiSita RamaswamySanjay TyagiYuri BushkinElke MühlbergerSuryaram GummuluruExacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the primary target cells of SARS-CoV-2 infection in humans, viral RNA and antigens in activated monocytes and macrophages have been detected in post-mortem samples, and dysfunctional monocytes and macrophages have been hypothesized to contribute to a protracted hyper-inflammatory state in COVID-19 patients. In this study, we demonstrate that CD169, a myeloid cell specific I-type lectin, facilitated ACE2-independent SARS-CoV-2 fusion and entry in macrophages. CD169-mediated SARS-CoV-2 entry in macrophages resulted in expression of viral genomic and subgenomic RNAs with minimal viral protein expression and no infectious viral particle release, suggesting a post-entry restriction of the SARS-CoV-2 replication cycle. Intriguingly this post-entry replication block was alleviated by exogenous ACE2 expression in macrophages. Restricted expression of viral genomic and subgenomic RNA in CD169+ macrophages elicited a pro-inflammatory cytokine expression (TNFα, IL-6 and IL-1β) in a RIG-I, MDA-5 and MAVS-dependent manner, which was suppressed by remdesivir treatment. These findings suggest that de novo expression of SARS-CoV-2 RNA in macrophages contributes to the pro-inflammatory cytokine signature and that blocking CD169-mediated ACE2 independent infection and subsequent activation of macrophages by viral RNA might alleviate COVID-19-associated hyperinflammatory response.https://doi.org/10.1371/journal.ppat.1010479 |
| spellingShingle | Sallieu Jalloh Judith Olejnik Jacob Berrigan Annuurun Nisa Ellen L Suder Hisashi Akiyama Maohua Lei Sita Ramaswamy Sanjay Tyagi Yuri Bushkin Elke Mühlberger Suryaram Gummuluru CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses. PLoS Pathogens |
| title | CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses. |
| title_full | CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses. |
| title_fullStr | CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses. |
| title_full_unstemmed | CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses. |
| title_short | CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses. |
| title_sort | cd169 mediated restrictive sars cov 2 infection of macrophages induces pro inflammatory responses |
| url | https://doi.org/10.1371/journal.ppat.1010479 |
| work_keys_str_mv | AT sallieujalloh cd169mediatedrestrictivesarscov2infectionofmacrophagesinducesproinflammatoryresponses AT juditholejnik cd169mediatedrestrictivesarscov2infectionofmacrophagesinducesproinflammatoryresponses AT jacobberrigan cd169mediatedrestrictivesarscov2infectionofmacrophagesinducesproinflammatoryresponses AT annuurunnisa cd169mediatedrestrictivesarscov2infectionofmacrophagesinducesproinflammatoryresponses AT ellenlsuder cd169mediatedrestrictivesarscov2infectionofmacrophagesinducesproinflammatoryresponses AT hisashiakiyama cd169mediatedrestrictivesarscov2infectionofmacrophagesinducesproinflammatoryresponses AT maohualei cd169mediatedrestrictivesarscov2infectionofmacrophagesinducesproinflammatoryresponses AT sitaramaswamy cd169mediatedrestrictivesarscov2infectionofmacrophagesinducesproinflammatoryresponses AT sanjaytyagi cd169mediatedrestrictivesarscov2infectionofmacrophagesinducesproinflammatoryresponses AT yuribushkin cd169mediatedrestrictivesarscov2infectionofmacrophagesinducesproinflammatoryresponses AT elkemuhlberger cd169mediatedrestrictivesarscov2infectionofmacrophagesinducesproinflammatoryresponses AT suryaramgummuluru cd169mediatedrestrictivesarscov2infectionofmacrophagesinducesproinflammatoryresponses |