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Lower Airway Dysbiosis Augments Lung Inflammatory Injury in Mild-to-Moderate COPD

Sulaiman, Imran; Wu, Benjamin G; Chung, Matthew; Isaacs, Bradley; Tsay, Jun-Chieh J; Holub, Meredith; Barnett, Clea R; Kwok, Benjmain; Kugler, Matthias C; Natalini, Jake G; Singh, Shivani; Li, Yonghua; Schluger, Rosemary; Carpenito, Joseph; Collazo, Destiny; Perez, Luisanny; Kyeremateng, Yaa; Chang, Miao; Campbell, Christina D; Hansbro, Philip M; Oppenheimer, Beno W; Berger, Kenneth I; Goldring, Roberta M; Koralov, Sergei B; Weiden, Michael D; Xiao, Rui; D'Armiento, Jeanine; Clemente, Jose C; Ghedin, Elodie; Segal, Leopoldo N
RATIONALE/BACKGROUND:Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality and health care costs. Cigarette smoke is a causative factor, however not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advance stages. OBJECTIVE:Here we investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis. METHODS:We recruited 57 patients with >10 pack year smoking history: 26 had physiological evidence of COPD, 31 had normal lung function (smoker controls). Bronchoscopy sampled the upper airways (UA), lower airways (BAL) and environmental background (BKG). Samples were analyzed by 16S rRNA gene sequencing, whole genome, RNA metatranscriptome and host RNA transcriptome. A preclinical mouse model was used to evaluate the contributions of cigarette smoke and dysbiosis on lower airway inflammatory injury. MEASUREMENTS/MAIN RESULTS/RESULTS:Compared with smoker controls, microbiome analyses showed that the lower airways of subjects with COPD were enriched with common oral commensals. The lower airway host transcriptomics demonstrated differences in markers of inflammation and tumorigenesis such as upregulation of IL-17, IL-6, ERK/MAPK, PI3K, MUC1 and MUC4 in mild-to-moderate COPD. Finally, in a pre-clinical murine model exposed to cigarette smoke, lower airway dysbiosis with common oral commensals augments the inflammatory injury revealing transcriptomic signatures similar to those observed in human COPD subjects. CONCLUSIONS:Lower airway dysbiosis in the setting of smoke exposure contributes to inflammatory injury early in COPD. Targeting the lower airway microbiome in combination with smoking cessation may be of potential therapeutic relevance.
PMID: 37677136
ISSN: 1535-4970
CID: 5573582

Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma

Dolgalev, Igor; Zhou, Hua; Murrell, Nina; Le, Hortense; Sakellaropoulos, Theodore; Coudray, Nicolas; Zhu, Kelsey; Vasudevaraja, Varshini; Yeaton, Anna; Goparaju, Chandra; Li, Yonghua; Sulaiman, Imran; Tsay, Jun-Chieh J; Meyn, Peter; Mohamed, Hussein; Sydney, Iris; Shiomi, Tomoe; Ramaswami, Sitharam; Narula, Navneet; Kulicke, Ruth; Davis, Fred P; Stransky, Nicolas; Smolen, Gromoslaw A; Cheng, Wei-Yi; Cai, James; Punekar, Salman; Velcheti, Vamsidhar; Sterman, Daniel H; Poirier, J T; Neel, Ben; Wong, Kwok-Kin; Chiriboga, Luis; Heguy, Adriana; Papagiannakopoulos, Thales; Nadorp, Bettina; Snuderl, Matija; Segal, Leopoldo N; Moreira, Andre L; Pass, Harvey I; Tsirigos, Aristotelis
Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.
PMID: 37938580
ISSN: 2041-1723
CID: 5577352

Microbial Inflammatory Networks in Bronchiectasis Exacerbators With Pseudomonas aeruginosa

Gramegna, Andrea; Narayana, Jayanth Kumar; Amati, Francesco; Stainer, Anna; Wu, Benjamin; Morlacchi, Letizia Corinna; Segal, Leopoldo N; Tsaneva-Atanasova, Krasimira; Marchisio, Paola; Chotirmall, Sanjay H; Blasi, Francesco; Aliberti, Stefano
PMID: 36803648
ISSN: 1931-3543
CID: 5433742

Correcting dysbiosis in the lungs of COPD, one pathogen at a time

Wong, Kendrew K; Segal, Leopoldo N
In this issue of Cell Host & Microbe, Liang et al. demonstrate through genomic analysis of the sputum microbiome from COPD patients and preclinical models that Staphylococcus aureus promotes lung function decline via regulation of homocysteine levels. Homocysteine can promote lung injury by promoting neutrophil apoptosis-to-NETosis shift via AKT1-S100A8/A9 axis.
PMID: 37321178
ISSN: 1934-6069
CID: 5541012

Perceived Hospital Stress, Severe Acute Respiratory Syndrome Coronavirus 2 Activity, and Care Process Temporal Variance During the COVID-19 Pandemic

Anesi, George L; Andrews, Adair; Bai, He Julia; Bhatraju, Pavan K; Brett-Major, David M; Broadhurst, M Jana; Campbell, Elizabeth Salvagio; Cobb, J Perren; Gonzalez, Martin; Homami, Sonya; Hypes, Cameron D; Irwin, Amy; Kratochvil, Christopher J; Krolikowski, Kelsey; Kumar, Vishakha K; Landsittel, Douglas P; Lee, Richard A; Liebler, Janice M; Lutrick, Karen; Marts, Lucian T; Mosier, Jarrod M; Mukherjee, Vikramjit; Postelnicu, Radu; Rodina, Valentina; Segal, Leopoldo N; Sevransky, Jonathan E; Spainhour, Christine; Srivastava, Avantika; Uyeki, Timothy M; Wurfel, Mark M; Wyles, David; Evans, Laura
OBJECTIVES:The COVID-19 pandemic threatened standard hospital operations. We sought to understand how this stress was perceived and manifested within individual hospitals and in relation to local viral activity. DESIGN:Prospective weekly hospital stress survey, November 2020-June 2022. SETTING:Society of Critical Care Medicine's Discovery Severe Acute Respiratory Infection-Preparedness multicenter cohort study. SUBJECTS:Thirteen hospitals across seven U.S. health systems. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We analyzed 839 hospital-weeks of data over 85 pandemic weeks and five viral surges. Perceived overall hospital, ICU, and emergency department (ED) stress due to severe acute respiratory infection patients during the pandemic were reported by a mean of 43% ( sd , 36%), 32% (30%), and 14% (22%) of hospitals per week, respectively, and perceived care deviations in a mean of 36% (33%). Overall hospital stress was highly correlated with ICU stress (ρ = 0.82; p < 0.0001) but only moderately correlated with ED stress (ρ = 0.52; p < 0.0001). A county increase in 10 severe acute respiratory syndrome coronavirus 2 cases per 100,000 residents was associated with an increase in the odds of overall hospital, ICU, and ED stress by 9% (95% CI, 5-12%), 7% (3-10%), and 4% (2-6%), respectively. During the Delta variant surge, overall hospital stress persisted for a median of 11.5 weeks (interquartile range, 9-14 wk) after local case peak. ICU stress had a similar pattern of resolution (median 11 wk [6-14 wk] after local case peak; p = 0.59) while the resolution of ED stress (median 6 wk [5-6 wk] after local case peak; p = 0.003) was earlier. There was a similar but attenuated pattern during the Omicron BA.1 subvariant surge. CONCLUSIONS:During the COVID-19 pandemic, perceived care deviations were common and potentially avoidable patient harm was rare. Perceived hospital stress persisted for weeks after surges peaked.
PMID: 36790189
ISSN: 1530-0293
CID: 5448062

More than Mycobacterium tuberculosis: site-of-disease microbial communities, and their functional and clinical profiles in tuberculous lymphadenitis

Nyawo, Georgina R; Naidoo, Charissa C; Wu, Benjamin; Sulaiman, Imran; Clemente, Jose C; Li, Yonghua; Minnies, Stephanie; Reeve, Byron W P; Moodley, Suventha; Rautenbach, Cornelia; Wright, Colleen; Singh, Shivani; Whitelaw, Andrew; Schubert, Pawel; Warren, Robin; Segal, Leopoldo; Theron, Grant
BACKGROUND:Lymphadenitis is the most common extrapulmonary tuberculosis (EPTB) manifestation. The microbiome is important to human health but uninvestigated in EPTB. We profiled the site-of-disease lymph node microbiome in tuberculosis lymphadenitis (TBL). METHODS:Fine-needle aspiration biopsies were collected from 158 pretreatment presumptive TBL patients in Cape Town, South Africa. 16S Illumina MiSeq rRNA gene sequencing was done. RESULTS:complex. CONCLUSIONS:-dominated dTBL lymphotypes, which contain taxa potentially targeted by TB treatment, were associated with milder, potentially earlier stage disease. These investigations lay foundations for studying the microbiome's role in lymphatic TB. The long-term clinical significance of these lymphotypes requires prospective validation.
PMID: 36598079
ISSN: 1468-3296
CID: 5441292

Pleural fluid microbiota as a biomarker for malignancy and prognosis

Kwok, Benjamin; Wu, Benjamin G; Kocak, Ibrahim F; Sulaiman, Imran; Schluger, Rosemary; Li, Yonghua; Anwer, Raheel; Goparaju, Chandra; Ryan, Daniel J; Sagatelian, Marla; Dreier, Matthew S; Murthy, Vivek; Rafeq, Samaan; Michaud, Gaetane C; Sterman, Daniel H; Bessich, Jamie L; Pass, Harvey I; Segal, Leopoldo N; Tsay, Jun-Chieh J
Malignant pleural effusions (MPE) complicate malignancies and portend worse outcomes. MPE is comprised of various components, including immune cells, cancer cells, and cell-free DNA/RNA. There have been investigations into using these components to diagnose and prognosticate MPE. We hypothesize that the microbiome of MPE is unique and may be associated with diagnosis and prognosis. We compared the microbiota of MPE against microbiota of pleural effusions from non-malignant and paramalignant states. We collected a total of 165 pleural fluid samples from 165 subjects; Benign (n = 16), Paramalignant (n = 21), MPE-Lung (n = 57), MPE-Other (n = 22), and Mesothelioma (n = 49). We performed high throughput 16S rRNA gene sequencing on pleural fluid samples and controls. We showed that there are compositional differences among pleural effusions related to non-malignant, paramalignant, and malignant disease. Furthermore, we showed differential enrichment of bacterial taxa within MPE depending on the site of primary malignancy. Pleural fluid of MPE-Lung and Mesothelioma were associated with enrichment with oral and gut bacteria that are commonly thought to be commensals, including Rickettsiella, Ruminococcus, Enterococcus, and Lactobacillales. Mortality in MPE-Lung is associated with enrichment in Methylobacterium, Blattabacterium, and Deinococcus. These observations lay the groundwork for future studies that explore host-microbiome interactions and their influence on carcinogenesis.
PMID: 36755121
ISSN: 2045-2322
CID: 5426932

Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity

Bhatraju, Pavan K.; Morrell, Eric D.; Stanaway, Ian B.; Sathe, Neha A.; Srivastava, Avantika; Postelnicu, Radu; Green, Richard; Andrews, Adair; Gonzalez, Martin; Kratochvil, Christopher J.; Kumar, Vishakha K.; Hsiang, Tien Ying; Gale, Michael; Anesi, George L.; Wyles, David; Broadhurst, M. Jana; Brett-Major, David; Mukherjee, Vikramjit; Sevransky, Jonathan E.; Landsittel, Douglas; Hung, Chi; Altemeier, William A.; Gharib, Sina A.; Uyeki, Timothy M.; Cobb, J. Perren; Liebler, Janice M.; Crosslin, David R.; Jarvik, Gail P.; Segal, Leopoldo N.; Evans, Laura; Mikacenic, Carmen; Wurfel, Mark M.
IMPORTANCE: Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES: To assess the role of ANGPTL4 in COVID-19-related outcomes. DESIGN, SETTING, AND PARTICIPANTS: Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES: Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS: Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log2increase, 1.53; 95% CI, 1.17-2.00; p = 0.002). Higher ANGPTL4 concentrations were also associated with higher proportions of venous thromboembolism and acute respiratory distress syndrome. Longitudinal ANGPTL4 concentrations were significantly different during the first 2 weeks of hospitalization in patients who subsequently died compared with survivors (p for interaction = 8.1 × 10-5). Proteomics analysis demonstrated abundance of ANGPTL4 in lung tissue compared with other organs in COVID-19. ANGPTL4 single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls. CONCLUSIONS AND RELEVANCE: ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients.
ISSN: 2639-8028
CID: 5424302

The dynamic lung microbiome in health and disease

Natalini, Jake G; Singh, Shivani; Segal, Leopoldo N
New methods and technologies within the field of lung biology are beginning to shed new light into the microbial world of the respiratory tract. Long considered to be a sterile environment, it is now clear that the human lungs are frequently exposed to live microbes and their by-products. The nature of the lung microbiome is quite distinct from other microbial communities inhabiting our bodies such as those in the gut. Notably, the microbiome of the lung exhibits a low biomass and is dominated by dynamic fluxes of microbial immigration and clearance, resulting in a bacterial burden and microbiome composition that is fluid in nature rather than fixed. As our understanding of the microbial ecology of the lung improves, it is becoming increasingly apparent that certain disease states can disrupt the microbial-host interface and ultimately affect disease pathogenesis. In this Review, we provide an overview of lower airway microbial dynamics in health and disease and discuss future work that is required to uncover novel therapeutic targets to improve lung health.
PMID: 36385637
ISSN: 1740-1534
CID: 5368872

The lung microbiome, peripheral gene expression, and recurrence-free survival after resection of stage II non-small cell lung cancer

Peters, Brandilyn A; Pass, Harvey I; Burk, Robert D; Xue, Xiaonan; Goparaju, Chandra; Sollecito, Christopher C; Grassi, Evan; Segal, Leopoldo N; Tsay, Jun-Chieh J; Hayes, Richard B; Ahn, Jiyoung
BACKGROUND:Cancer recurrence after tumor resection in early-stage non-small cell lung cancer (NSCLC) is common, yet difficult to predict. The lung microbiota and systemic immunity may be important modulators of risk for lung cancer recurrence, yet biomarkers from the lung microbiome and peripheral immune environment are understudied. Such markers may hold promise for prediction as well as improved etiologic understanding of lung cancer recurrence. METHODS:In tumor and distant normal lung samples from 46 stage II NSCLC patients with curative resection (39 tumor samples, 41 normal lung samples), we conducted 16S rRNA gene sequencing. We also measured peripheral blood immune gene expression with nanoString®. We examined associations of lung microbiota and peripheral gene expression with recurrence-free survival (RFS) and disease-free survival (DFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression, and examined predictive accuracy using time-dependent receiver operating characteristic (ROC) curves. RESULTS:Over a median of 4.8 years of follow-up (range 0.2-12.2 years), 43% of patients experienced a recurrence, and 50% died. In normal lung tissue, a higher abundance of classes Bacteroidia and Clostridia, and orders Bacteroidales and Clostridiales, were associated with worse RFS, while a higher abundance of classes Alphaproteobacteria and Betaproteobacteria, and orders Burkholderiales and Neisseriales, were associated with better RFS. In tumor tissue, a higher abundance of orders Actinomycetales and Pseudomonadales were associated with worse DFS. Among these taxa, normal lung Clostridiales and Bacteroidales were also related to worse survival in a previous small pilot study and an additional independent validation cohort. In peripheral blood, higher expression of genes TAP1, TAPBP, CSF2RB, and IFITM2 were associated with better DFS. Analysis of ROC curves revealed that lung microbiome and peripheral gene expression biomarkers provided significant additional recurrence risk discrimination over standard demographic and clinical covariates, with microbiome biomarkers contributing more to short-term (1-year) prediction and gene biomarkers contributing to longer-term (2-5-year) prediction. CONCLUSIONS:We identified compelling biomarkers in under-explored data types, the lung microbiome, and peripheral blood gene expression, which may improve risk prediction of recurrence in early-stage NSCLC patients. These findings will require validation in a larger cohort.
PMID: 36303210
ISSN: 1756-994x
CID: 5358192