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  1. Article ; Online: A viral assembly inhibitor blocks SARS-CoV-2 replication in airway epithelial cells.

    Du, Li / Deiter, Fred / Bouzidi, Mohamed S / Billaud, Jean-Noël / Simmons, Graham / Dabral, Prerna / Selvarajah, Suganya / Lingappa, Anuradha F / Michon, Maya / Yu, Shao Feng / Paulvannan, Kumar / Manicassamy, Balaji / Lingappa, Vishwanath R / Boushey, Homer / Greenland, John R / Pillai, Satish K

    Communications biology

    2024  Volume 7, Issue 1, Page(s) 486

    Abstract: The ongoing evolution of SARS-CoV-2 to evade vaccines and therapeutics underlines the need for innovative therapies with high genetic barriers to resistance. Therefore, there is pronounced interest in identifying new pharmacological targets in the SARS- ... ...

    Abstract The ongoing evolution of SARS-CoV-2 to evade vaccines and therapeutics underlines the need for innovative therapies with high genetic barriers to resistance. Therefore, there is pronounced interest in identifying new pharmacological targets in the SARS-CoV-2 viral life cycle. The small molecule PAV-104, identified through a cell-free protein synthesis and assembly screen, was recently shown to target host protein assembly machinery in a manner specific to viral assembly. In this study, we investigate the capacity of PAV-104 to inhibit SARS-CoV-2 replication in human airway epithelial cells (AECs). We show that PAV-104 inhibits >99% of infection with diverse SARS-CoV-2 variants in immortalized AECs, and in primary human AECs cultured at the air-liquid interface (ALI) to represent the lung microenvironment in vivo. Our data demonstrate that PAV-104 inhibits SARS-CoV-2 production without affecting viral entry, mRNA transcription, or protein synthesis. PAV-104 interacts with SARS-CoV-2 nucleocapsid (N) and interferes with its oligomerization, blocking particle assembly. Transcriptomic analysis reveals that PAV-104 reverses SARS-CoV-2 induction of the type-I interferon response and the maturation of nucleoprotein signaling pathway known to support coronavirus replication. Our findings suggest that PAV-104 is a promising therapeutic candidate for COVID-19 with a mechanism of action that is distinct from existing clinical management approaches.
    MeSH term(s) Humans ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology ; Virus Replication/drug effects ; Epithelial Cells/virology ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Antiviral Agents/pharmacology ; Virus Assembly/drug effects ; COVID-19/virology ; COVID-19 Drug Treatment
    Chemical Substances Antiviral Agents
    Language English
    Publishing date 2024-04-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-024-06130-8
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  2. Article ; Online: Human galectin-9 potently enhances SARS-CoV-2 replication and inflammation in airway epithelial cells.

    Du, Li / Bouzidi, Mohamed S / Gala, Akshay / Deiter, Fred / Billaud, Jean-Noël / Yeung, Stephen T / Dabral, Prerna / Jin, Jing / Simmons, Graham / Dossani, Zain Y / Niki, Toshiro / Ndhlovu, Lishomwa C / Greenland, John R / Pillai, Satish K

    Journal of molecular cell biology

    2023  Volume 15, Issue 4

    Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global economic and health crisis. Recently, plasma levels of galectin-9 (Gal-9), a β-galactoside-binding lectin involved in immune regulation and viral ... ...

    Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global economic and health crisis. Recently, plasma levels of galectin-9 (Gal-9), a β-galactoside-binding lectin involved in immune regulation and viral immunopathogenesis, were reported to be elevated in the setting of severe COVID-19 disease. However, the impact of Gal-9 on SARS-CoV-2 infection and immunopathology remained to be elucidated. In this study, we demonstrate that Gal-9 treatment potently enhances SARS-CoV-2 replication in human airway epithelial cells (AECs), including immortalized AECs and primary AECs cultured at the air-liquid interface. Gal-9-glycan interactions promote SARS-CoV-2 attachment and entry into AECs in an angiotensin-converting enzyme 2 (ACE2)-dependent manner, enhancing the binding of the viral spike protein to ACE2. Transcriptomic analysis revealed that Gal-9 and SARS-CoV-2 infection synergistically induced the expression of key pro-inflammatory programs in AECs, including the IL-6, IL-8, IL-17, EIF2, and TNFα signaling pathways. Our findings suggest that manipulation of Gal-9 should be explored as a therapeutic strategy for SARS-CoV-2 infection.
    MeSH term(s) Humans ; Angiotensin-Converting Enzyme 2 ; COVID-19/metabolism ; COVID-19/virology ; Epithelial Cells/metabolism ; Epithelial Cells/virology ; Galectins/metabolism ; Inflammation/metabolism ; Inflammation/virology ; SARS-CoV-2/physiology ; Virus Replication
    Chemical Substances Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Galectins
    Language English
    Publishing date 2023-05-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2500949-7
    ISSN 1759-4685 ; 1759-4685
    ISSN (online) 1759-4685
    ISSN 1759-4685
    DOI 10.1093/jmcb/mjad030
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  3. Article: A Novel Viral Assembly Inhibitor Blocks SARS-CoV-2 Replication in Airway Epithelial Cells.

    Pillai, Satish / Du, Li / Deiter, Fred / Bouzidi, Mohamed / Billaud, Jean-Noel / Graham, Simmons / Prerna, Dabral / Selvarajah, Suganya / Lingappa, Anuradha / Michon, Maya / Yu, Shao / Paulvannan, Kumar / Lingappa, Vishwanath / Boushey, Homer / Greenland, John

    Research square

    2023  

    Abstract: The ongoing evolution of SARS-CoV-2 to evade vaccines and therapeutics underlines the need for novel therapies with high genetic barriers to resistance. The small molecule PAV-104, identified through a cell-free protein synthesis and assembly screen, was ...

    Abstract The ongoing evolution of SARS-CoV-2 to evade vaccines and therapeutics underlines the need for novel therapies with high genetic barriers to resistance. The small molecule PAV-104, identified through a cell-free protein synthesis and assembly screen, was recently shown to target host protein assembly machinery in a manner specific to viral assembly. Here, we investigated the capacity of PAV-104 to inhibit SARS-CoV-2 replication in human airway epithelial cells (AECs). Our data demonstrate that PAV-104 inhibited > 99% of infection with diverse SARS-CoV-2 variants in primary and immortalized human AECs. PAV-104 suppressed SARS-CoV-2 production without affecting viral entry or protein synthesis. PAV-104 interacted with SARS-CoV-2 nucleocapsid (N) and interfered with its oligomerization, blocking particle assembly. Transcriptomic analysis revealed that PAV-104 reversed SARS-CoV-2 induction of the Type-I interferon response and the 'maturation of nucleoprotein' signaling pathway known to support coronavirus replication. Our findings suggest that PAV-104 is a promising therapeutic candidate for COVID-19.
    Language English
    Publishing date 2023-05-17
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-2887435/v1
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  4. Article ; Online: Biofire pneumonia panel in lung donors: faster detection but limited pathogens.

    Nguyen, Anh / Chen, Joy / Isaza, Erin / Panchal, Niel / Deiter, Fred / Hoover, Jonathan / Trinh, Binh / Hays, Steve R / Golden, Jeffrey A / Singer, Jonathan P / Brzezinski, Marek / Greenland, John R / Kukreja, Jasleen

    Transplant infectious disease : an official journal of the Transplantation Society

    2023  Volume 25, Issue 4, Page(s) e14091

    Abstract: Background: Culture of bronchoalveolar lavage (BAL) specimens takes time to report. We tested whether a molecular diagnostic test could accelerate donor lung assessment and treatment.: Methods: We compared BioFire Film Array Pneumonia Panel (BFPP) ... ...

    Abstract Background: Culture of bronchoalveolar lavage (BAL) specimens takes time to report. We tested whether a molecular diagnostic test could accelerate donor lung assessment and treatment.
    Methods: We compared BioFire Film Array Pneumonia Panel (BFPP) with standard of care (SOC) tests on lung allograft samples at three time points: (1) donor BAL at organ recovery, (2) donor bronchial tissue and airway swab at implantation, and (3) first recipient BAL following lung implantation. Primary outcomes were the difference in time to result (Wilcoxon signed-ranked tests) and the agreement in results between BFPP and SOC assays (Gwet's agreement coefficient).
    Results: We enrolled 50 subjects. In donor lung BAL specimens, BFPP detected 52 infections (14 out of 26 pathogens in the panel). Viral and bacterial BFPP results were reported 2.4 h (interquartile range, IQR 2.0-6.4) following BAL versus 4.6 h (IQR 1.9-6.0, p = 0.625) for OPO BAL viral SOC results and 66 h (IQR 47-87, p < .0001) for OPO BAL bacterial SOC results. Although there was high overall agreement of results between BAL-BFPP versus OPO BAL-SOC tests (Gwet's AC p < .001 for all), the level of agreement differed among 26 pathogens designed in BFPP and differed by types of specimens. BFPP could not detect many infections identified by SOC assays.
    Conclusions: BFPP decreased time to detection of lung pathogens among donated lungs, but it cannot replace SOC tests due to the limited number of pathogens in the panel.
    MeSH term(s) Humans ; Bronchoalveolar Lavage Fluid/microbiology ; Bronchoalveolar Lavage/methods ; Lung ; Pneumonia/diagnosis ; Bacteria ; Pneumonia, Bacterial
    Language English
    Publishing date 2023-07-10
    Publishing country Denmark
    Document type Journal Article
    ZDB-ID 1476094-0
    ISSN 1399-3062 ; 1398-2273
    ISSN (online) 1399-3062
    ISSN 1398-2273
    DOI 10.1111/tid.14091
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  5. Article: Human Galectin-9 Potently Enhances SARS-CoV-2 Replication and Inflammation in Airway Epithelial Cells.

    Du, Li / Bouzidi, Mohamed S / Gala, Akshay / Deiter, Fred / Billaud, Jean-Noël / Yeung, Stephen T / Dabral, Prerna / Jin, Jing / Simmons, Graham / Dossani, Zain / Niki, Toshiro / Ndhlovu, Lishomwa C / Greenland, John R / Pillai, Satish K

    bioRxiv : the preprint server for biology

    2022  

    Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global economic and health crisis. Recently, plasma levels of galectin-9 (Gal-9), a β-galactoside-binding lectin involved in immune regulation and viral ... ...

    Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global economic and health crisis. Recently, plasma levels of galectin-9 (Gal-9), a β-galactoside-binding lectin involved in immune regulation and viral immunopathogenesis, were reported to be elevated in the setting of severe COVID-19 disease. However, the impact of Gal-9 on SARS-CoV-2 infection and immunopathology remained to be elucidated. Here, we demonstrate that Gal-9 treatment potently enhances SARS-CoV-2 replication in human airway epithelial cells (AECs), including primary AECs in air-liquid interface (ALI) culture. Gal-9-glycan interactions promote SARS-CoV-2 attachment and entry into AECs in an ACE2-dependent manner, enhancing the binding affinity of the viral spike protein to ACE2. Transcriptomic analysis revealed that Gal-9 and SARS-CoV-2 infection synergistically induce the expression of key pro-inflammatory programs in AECs including the IL-6, IL-8, IL-17, EIF2, and TNFα signaling pathways. Our findings suggest that manipulation of Gal-9 should be explored as a therapeutic strategy for SARS-CoV-2 infection.
    Importance: COVID-19 continues to have a major global health and economic impact. Identifying host molecular determinants that modulate SARS-CoV-2 infectivity and pathology is a key step in discovering novel therapeutic approaches for COVID-19. Several recent studies have revealed that plasma concentrations of the human β-galactoside-binding protein galectin-9 (Gal-9) are highly elevated in COVID-19 patients. In this study, we investigated the impact of Gal-9 on SARS-CoV-2 pathogenesis
    Language English
    Publishing date 2022-05-16
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2022.03.18.484956
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  6. Article ; Online: Inflammation on bronchoalveolar lavage cytology is associated with decreased chronic lung allograft dysfunction-free survival.

    Greenland, Nancy Y / Deiter, Fred / Calabrese, Daniel R / Hays, Steven R / Kukreja, Jasleen / Leard, Lorriana E / Kolaitis, Nicholas A / Golden, Jeffrey A / Singer, Jonathan P / Greenland, John R

    Clinical transplantation

    2022  Volume 36, Issue 6, Page(s) e14639

    Abstract: Background: Lung transplant recipients undergo bronchoalveolar lavage (BAL) to detect antecedents of chronic lung allograft dysfunction (CLAD), but routine assessment of BAL cytology is controversial. We hypothesized that inflammation on BAL cytology ... ...

    Abstract Background: Lung transplant recipients undergo bronchoalveolar lavage (BAL) to detect antecedents of chronic lung allograft dysfunction (CLAD), but routine assessment of BAL cytology is controversial. We hypothesized that inflammation on BAL cytology would predict CLAD-free survival.
    Methods: In a single-center retrospective cohort, associations between cytology results and clinical characteristics were compared using generalized-estimating equation-adjusted regression. The association between BAL inflammation and CLAD or death risk was assessed using time-dependent Cox models.
    Results: In 3365 cytology reports from 451 subjects, inflammation was the most common finding (6.2%, 210 cases), followed by fungal forms (5.3%, 178 cases, including 24 cases of suspected Aspergillus). Inflammation on BAL cytology was more common in procedures for symptoms (8.5%) versus surveillance (3.2%, p < .001). Inflammation on cytology was associated with automated neutrophil and lymphocyte counts, acute cellular rejection, infection, and portended a 2.2-fold hazard ratio (CI 1.2-4.0, p = .007) for CLAD or death. However, inflammation by cytology did not inform CLAD-free survival risk beyond automated BAL cell counts (p = .57).
    Conclusions: Inflammation on BAL cytology is clinically significant, suggesting acute rejection or infection and increased risk of CLAD or death. However, other indicators of allograft inflammation can substitute for much of the information provided by BAL cytology.
    MeSH term(s) Allografts ; Bronchoalveolar Lavage ; Bronchoalveolar Lavage Fluid ; Graft Rejection/diagnosis ; Graft Rejection/etiology ; Graft vs Host Disease/etiology ; Humans ; Inflammation/etiology ; Lung ; Lung Transplantation/adverse effects ; Retrospective Studies
    Language English
    Publishing date 2022-03-12
    Publishing country Denmark
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ZDB-ID 639001-8
    ISSN 1399-0012 ; 0902-0063
    ISSN (online) 1399-0012
    ISSN 0902-0063
    DOI 10.1111/ctr.14639
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  7. Article ; Online: Rapid molecular detection of airway pathogens in lung transplant recipients.

    Hoover, Jonathan / Mintz, Michelle A / Deiter, Fred / Aminian, Emily / Chen, Joy / Hays, Steven R / Singer, Jonathan P / Calabrese, Daniel R / Kukreja, Jasleen / Greenland, John R

    Transplant infectious disease : an official journal of the Transplantation Society

    2021  Volume 23, Issue 4, Page(s) e13579

    Abstract: Background: Airway infections are difficult to distinguish from acute rejection in lung transplant recipients. Traditional culture techniques take time that may delay treatment. We hypothesized that a rapid multiplex molecular assay could improve time ... ...

    Abstract Background: Airway infections are difficult to distinguish from acute rejection in lung transplant recipients. Traditional culture techniques take time that may delay treatment. We hypothesized that a rapid multiplex molecular assay could improve time to diagnosis and appropriate clinical decision making.
    Methods: In a prospective observational study of recipients undergoing bronchoscopy, we assessed the BioFire
    Results: For the 150 enrolled subjects, BFPP results were available 3.8 hours (IQR 2.8-5.1) following bronchoscopy, compared to 13 hours for viral SOC (IQR 10-34, P < .001) results and 48 hours for bacterial SOC (IQR 46-70, P < .001) results. Positive BFPP results were interpreted in 9 hours (IQR 5-20) following bronchoscopy, compared to 74 hours for SOC (IQR 37-110, P < .001). Assays agreed for 138 (92%) of the 150 subjects. Of 22 BFPP diagnoses, five (23%) resulted in a shadow antibiotic recommendation. Notable BFPP deficiencies included fungal species and H parainfluenzae, accounting for 15 (27%) and 13 (23%) of the 56 actionable SOC results, respectively.
    Conclusions: This molecular diagnostic including bacterial targets has the potential to shorten time to diagnosis and augment current clinical decision making but cannot replace SOC culture methods.
    MeSH term(s) Bacteria/genetics ; Fungi ; Humans ; Lung ; Pneumonia ; Transplant Recipients
    Language English
    Publishing date 2021-02-18
    Publishing country Denmark
    Document type Journal Article ; Observational Study
    ZDB-ID 1476094-0
    ISSN 1399-3062 ; 1398-2273
    ISSN (online) 1399-3062
    ISSN 1398-2273
    DOI 10.1111/tid.13579
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  8. Article ; Online: Human Galectin-9 Potently Enhances SARS-CoV-2 Replication and Inflammation in Airway Epithelial Cells

    Du, Li / Bouzidi, Mohamed S. / Gala, Akshay / Deiter, Fred / Billaud, Jean-Noel / Yeung, Stephen / Dabral, Prerna / Jin, Jing / Simmons, Graham / Dossani, Zain / Niki, Toshiro / Ndhlovu, Lishomwa / Greenland, John / Pillai, Satish K

    bioRxiv

    Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global economic and health crisis. Recently, plasma levels of galectin-9 (Gal-9), a β-galactoside-binding lectin involved in immune regulation and viral ... ...

    Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global economic and health crisis. Recently, plasma levels of galectin-9 (Gal-9), a β-galactoside-binding lectin involved in immune regulation and viral immunopathogenesis, were reported to be elevated in the setting of severe COVID-19 disease. However, the impact of Gal-9 on SARS-CoV-2 infection and immunopathology remained to be elucidated. Here, we demonstrate that Gal-9 treatment potently enhances SARS-CoV-2 replication in human airway epithelial cells (AECs), including primary AECs in air-liquid interface (ALI) culture. Gal-9 promotes SARS-CoV-2 attachment and entry into AECs in an ACE2-dependent manner, enhancing the binding affinity of the viral spike protein to ACE2. Transcriptomic analysis revealed that Gal-9 and SARS-CoV-2 infection synergistically induced the expression of key pro-inflammatory programs in AECs including the IL-6, IL-8, IL-17, EIF2, and TNFα signaling pathways. Our findings suggest that manipulation of Gal-9 should be explored as a therapeutic strategy for SARS-CoV-2 infection.
    Keywords covid19
    Language English
    Publishing date 2022-03-20
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2022.03.18.484956
    Database COVID19

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  9. Article ; Online: Lung Allograft Epithelium DNA Methylation Age Is Associated With Graft Chronologic Age and Primary Graft Dysfunction.

    Dugger, Daniel T / Calabrese, Daniel R / Gao, Ying / Deiter, Fred / Tsao, Tasha / Maheshwari, Julia / Hays, Steven R / Leard, Lorriana / Kleinhenz, Mary Ellen / Shah, Rupal / Golden, Jeff / Kukreja, Jasleen / Gordon, Erin D / Singer, Jonathan P / Greenland, John R

    Frontiers in immunology

    2021  Volume 12, Page(s) 704172

    Abstract: Advanced donor age is a risk factor for poor survival following lung transplantation. However, recent work identifying epigenetic determinants of aging has shown that biologic age may not always reflect chronologic age and that stressors can accelerate ... ...

    Abstract Advanced donor age is a risk factor for poor survival following lung transplantation. However, recent work identifying epigenetic determinants of aging has shown that biologic age may not always reflect chronologic age and that stressors can accelerate biologic aging. We hypothesized that lung allografts that experienced primary graft dysfunction (PGD), characterized by poor oxygenation in the first three post-transplant days, would have increased biologic age. We cultured airway epithelial cells isolated by transbronchial brush at 1-year bronchoscopies from 13 subjects with severe PGD and 15 controls matched on age and transplant indication. We measured epigenetic age using the Horvath epigenetic clock. Linear models were used to determine the association of airway epigenetic age with chronologic ages and PGD status, adjusted for recipient PGD risk factors. Survival models assessed the association with chronic lung allograft dysfunction (CLAD) or death. Distributions of promoter methylation within pathways were compared between groups. DNA methyltransferase (DNMT) activity was quantified in airway epithelial cells under hypoxic or normoxic conditions. Airway epigenetic age appeared younger but was strongly associated with the age of the allograft (slope 0.38 per year, 95% CI 0.27-0.48). There was no correlation between epigenetic age and recipient age (P = 0.96). Epigenetic age was 6.5 years greater (95% CI 1.7-11.2) in subjects who had experienced PGD, and this effect remained significant after adjusting for donor and recipient characteristics (P = 0.03). Epigenetic age was not associated with CLAD-free survival risk (P = 0.11). Analysis of differential methylation of promoters of key biologic pathways revealed hypomethylation in regions related to hypoxia, inflammation, and metabolism-associated pathways. Accordingly, airway epithelial cells cultured in hypoxic conditions showed suppressed DNMT activity. While airway methylation age was primarily determined by donor chronologic age, early injury in the form of PGD was associated with increased allograft epigenetic age. These data show how PGD might suppress key promoter methylation resulting in long-term impacts on the allograft.
    MeSH term(s) Adult ; Age Factors ; Aged ; Allografts ; DNA Methylation ; Disease-Free Survival ; Female ; Humans ; Lung/metabolism ; Lung Transplantation ; Male ; Middle Aged ; Models, Biological ; Primary Graft Dysfunction/metabolism ; Primary Graft Dysfunction/mortality ; Respiratory Mucosa/metabolism ; Risk Assessment ; Risk Factors ; Survival Rate
    Language English
    Publishing date 2021-10-07
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2021.704172
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  10. Article ; Online: Chronic lung allograft dysfunction small airways reveal a lymphocytic inflammation gene signature.

    Dugger, Daniel T / Fung, Monica / Hays, Steven R / Singer, Jonathan P / Kleinhenz, Mary E / Leard, Lorriana E / Golden, Jeffrey A / Shah, Rupal J / Lee, Joyce S / Deiter, Fred / Greenland, Nancy Y / Jones, Kirk D / Langelier, Chaz R / Greenland, John R

    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

    2020  Volume 21, Issue 1, Page(s) 362–371

    Abstract: Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term survival following lung transplantation, and new mechanistic biomarkers are needed. Lymphocytic bronchitis (LB) precedes CLAD and has a defined molecular signature. We ... ...

    Abstract Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term survival following lung transplantation, and new mechanistic biomarkers are needed. Lymphocytic bronchitis (LB) precedes CLAD and has a defined molecular signature. We hypothesized that this LB molecular signature would be associated with CLAD in small airway brushings independent of infection. We quantified RNA expression from small airway brushings and transbronchial biopsies, using RNAseq and digital RNA counting, respectively, for 22 CLAD cases and 27 matched controls. LB metagene scores were compared across CLAD strata by Wilcoxon rank sum test. We performed unbiased host transcriptome pathway and microbial metagenome analysis in airway brushes and compared machine-learning classifiers between the two tissue types. This LB metagene score was increased in CLAD airway brushes (p = .002) and improved prediction of graft failure (p = .02). Gene expression classifiers based on airway brushes outperformed those using transbronchial biopsies. While infection was associated with decreased microbial alpha-diversity (p ≤ .04), neither infection nor alpha-diversity was associated with LB gene expression. In summary, CLAD was associated with small airway gene expression changes not apparent in transbronchial biopsies in this cohort. Molecular analysis of airway brushings for diagnosing CLAD merits further examination in multicenter cohorts.
    MeSH term(s) Allografts ; Graft Rejection/genetics ; Humans ; Inflammation/genetics ; Lung ; Lung Transplantation/adverse effects
    Language English
    Publishing date 2020-09-22
    Publishing country United States
    Document type Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2060594-8
    ISSN 1600-6143 ; 1600-6135
    ISSN (online) 1600-6143
    ISSN 1600-6135
    DOI 10.1111/ajt.16293
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