SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-g and NK cells
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ABSTRACT:
PROVIDER: PRJNA1019722 | ENA |
REPOSITORIES: ENA
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Project description:SARS-CoV-2 RNA generally becomes undetectable in upper airways after a few days or weeks post-infection. It is unclear however if the virus persists in other parts of the body and which mechanism(s) regulate SARS-CoV-2 persistence. We addressed this question in the macaque model. Replication-competent virus was detected in bronchioalveolar lavages (BAL) macrophages beyond 6 months post-infection. SARS-CoV-2 propagated in BAL macrophages from cell-to-cell. IFN-γ inhibited this replication. IFN-γ production within BAL lymphocytes was strongest in NKG2r+CD8+ T and NKG2Alo NK cells and was further increased in NKG2Alo NK cells after Spike protein stimulation. However, IFN-γ production was impaired in NK cells from animals with persisting virus. IFN-γ also enhanced MHC-E expression on BAL macrophages, possibly inhibiting natural killer cell mediated killing. Animals with less persisting virus mounted adaptive NK cells escaping this MHC-E dependent inhibition. Our findings reveal an interplay between NK cells and macrophages mediated by IFN-γ, regulating SARS-CoV-2 persistence in macrophages. Gene expression in bronchoalveolar lavage fluid (BALF) NK cells in SARS-CoV-2 convalescent monkeys.
2023-09-25 | GSE243733 | GEO
Project description:SARS-CoV-2 RNA generally becomes undetectable in upper airways after a few days or weeks post-infection. It is unclear however if the virus persists in other parts of the body and which mechanism(s) regulate SARS-CoV-2 persistence. We addressed this question in the macaque model. Replication-competent virus was detected in bronchioalveolar lavages (BAL) macrophages beyond 6 months post-infection. SARS-CoV-2 propagated in BAL macrophages from cell-to-cell. IFN-γ inhibited this replication. IFN-γ production within BAL lymphocytes was strongest in NKG2r+CD8+ T and NKG2Alo NK cells and was further increased in NKG2Alo NK cells after Spike protein stimulation. However, IFN-γ production was impaired in NK cells from animals with persisting virus. IFN-γ also enhanced MHC-E expression on BAL macrophages, possibly inhibiting natural killer cell mediated killing. Animals with less persisting virus mounted adaptive NK cells escaping this MHC-E dependent inhibition. Our findings reveal an interplay between NK cells and macrophages mediated by IFN-γ, regulating SARS-CoV-2 persistence in macrophages. Gene expression in bronchoalveolar lavage fluid (BALF) NK cells in SARS-CoV-2 convalescent monkeys.
2023-09-25 | GSE243732 | GEO
Project description:SARS-CoV-2 RNA generally becomes undetectable in upper airways after a few days or weeks post-infection. It is unclear however if the virus persists in other parts of the body and which mechanism(s) regulate SARS-CoV-2 persistence. We addressed this question in the macaque model. Replication-competent virus was detected in bronchioalveolar lavages (BAL) macrophages beyond 6 months post-infection. SARS-CoV-2 propagated in BAL macrophages from cell-to-cell. IFN-γ inhibited this replication. IFN-γ production within BAL lymphocytes was strongest in NKG2r+CD8+ T and NKG2Alo NK cells and was further increased in NKG2Alo NK cells after Spike protein stimulation. However, IFN-γ production was impaired in NK cells from animals with persisting virus. IFN-γ also enhanced MHC-E expression on BAL macrophages, possibly inhibiting natural killer cell mediated killing. Animals with less persisting virus mounted adaptive NK cells escaping this MHC-E dependent inhibition. Our findings reveal an interplay between NK cells and macrophages mediated by IFN-γ, regulating SARS-CoV-2 persistence in macrophages. Gene expression in bronchoalveolar lavage fluid (BALF) CD64+ Macrophages isolated from 6 healthy donors, 5 randomly chosen wuhan- and 10 omicron infected cynomolgus macaques at least 221 days post-infection, cultured for 8h and profiled with the NanoString nCounter System.
2023-09-25 | GSE243731 | GEO
Project description:SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-g and NK cells [BALF_Macro_SARS_NHP]
| PRJNA1019726 | ENA
Project description:SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-g and NK cells [BALF_BloodNK_SARSWu_NHP]
| PRJNA1019728 | ENA
Project description:SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-g and NK cells [BALF_NK_SARSWu_NHP]
| PRJNA1019727 | ENA
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection. Here we used a model of viral infection in macaques to address whether SARS-CoV-2 persists in the body and which mechanisms regulate its persistence. Replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages beyond 6 months postinfection. Viral propagation in BAL macrophages occurred from cell to cell and was inhibited by interferon-γ (IFN-γ). IFN-γ production was strongest in BAL NKG2r+CD8+ T cells and NKG2Alo natural killer (NK) cells and was further increased in NKG2Alo NK cells after spike protein stimulation. However, IFN-γ production was impaired in NK cells from macaques with persisting virus. Moreover, IFN-γ also enhanced the expression of major histocompatibility complex (MHC)-E on BAL macrophages, possibly inhibiting NK cell-mediated killing. Macaques with less persisting virus mounted adaptive NK cells that escaped the MHC-E-dependent inhibition. Our findings reveal an interplay between NK cells and macrophages that regulated SARS-CoV-2 persistence in macrophages and was mediated by IFN-γ.
| S-EPMC10681903 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-09-25 | GSE243734 | GEO
Project description:The anti-leukemia activity of NK cells helps to prevent relapse during hematopoietic stem cell transplantation in leukemia patients. However, the factors that determine sensitivity or resistance of leukemia cells in the context of NK-mediated cytotoxicity are not well established. Here we performed a genome-wide CRIPSR screen in the human chronic-myelogenous-leukemia (CML) cell line K562 to identify genes that regulate vulnerability of leukemia cells to killing by primary human NK cells. Distribution of guide RNAs (gRNAs) in K562 cells that survived co-incubation with NK cells showed that loss of NCR3LG1, which encodes the ligand of the natural cytotoxicity receptor NKp30, protected K562 cells from killing. In contrast, loss of genes that regulate pathways for antigen-presentation and interferon-gamma-signaling increased the vulnerability of K562 cells. Addition of IFN-gamma neutralizing antibody increased the susceptibility of K562 cells to NK-mediated killing. Upregulation of MHC class I on K562 cells after co-incubation with NK cells was dependent on IFNGR2. Analysis of RNA-seq data from The Cancer Genome Atlas (TCGA) showed that low IFNGR2 expression in cancer tissues associated with improved overall survival in acute myeloid leukemia (AML) and Kidney Renal Clear Cell Carcinoma (KIRC) patients. Our results showing that upregulation of MHC class I by NK-derived IFN-gamma leads to resistance to NK cytotoxicity suggest that targeting IFN-gamma responses might be a promising approach to enhance NK cell anti-cancer efficacy.
2019-10-24 | GSE139313 | GEO
Project description:Macrophage activation syndrome (MAS) is a life-threatening cytokine storm syndrome complicating systemic juvenile idiopathic arthritis (SJIA) and driven by IFN-gamma. SJIA and MAS are also associated with an unexplained emerging inflammatory lung disease (SJIA-LD), with our recent work supporting pulmonary activation of IFN-gamma pathways as a pathologic link between SJIA-LD and MAS. Our objective was to mechanistically define the novel observation of pulmonary inflammation in the TLR9 mouse model of MAS. In acute MAS, lungs exhibit mild but diffuse CD4-predominant, perivascular interstitial inflammation with elevated IFN-gamma, IFN-induced chemokines, and alveolar macrophage expression of IFN-gamma-induced genes. Single-cell RNA-sequencing confirmed IFN-driven transcriptional changes across immune and parenchymal lung cell types. Resolution of MAS was associated with increased alveolar macrophage and interstitial lymphocytic infiltration. alveolar macrophage microarrays confirmed IFN-gamma-induced proinflammatory polarization during acute MAS, which switches towards an anti-inflammatory phenotype during MAS resolution. Interestingly, recurrent MAS led to increased alveolar inflammation and lung injury, and reset alveolar macrophagepolarization towards a proinflammatory state. Furthermore, in mice bearing macrophages insensitive to IFN-gamma, both systemic feature of MAS and pulmonary inflammation were attenuated. These findings demonstrate that experimental MAS induces IFN-gamma-driven pulmonary inflammation replicating key features of SJIA-LD, and provides a model system for testing novel treatments directed towards SJIA-LD.
2021-09-12 | GSE169325 | GEO