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Pathobiological signatures of dysbiotic lung injury in pediatric patients undergoing stem cell transplantation
Zinter, Matt S; Dvorak, Christopher C; Mayday, Madeline Y; Reyes, Gustavo; Simon, Miriam R; Pearce, Emma M; Kim, Hanna; Shaw, Peter J; Rowan, Courtney M; Auletta, Jeffrey J; Martin, Paul L; Godder, Kamar; Duncan, Christine N; Lalefar, Nahal R; Kreml, Erin M; Hume, Janet R; Abdel-Azim, Hisham; Hurley, Caitlin; Cuvelier, Geoffrey D E; Keating, Amy K; Qayed, Muna; Killinger, James S; Fitzgerald, Julie C; Hanna, Rabi; Mahadeo, Kris M; Quigg, Troy C; Satwani, Prakash; Castillo, Paul; Gertz, Shira J; Moore, Theodore B; Hanisch, Benjamin; Abdel-Mageed, Aly; Phelan, Rachel; Davis, Dereck B; Hudspeth, Michelle P; Yanik, Greg A; Pulsipher, Michael A; Sulaiman, Imran; Segal, Leopoldo N; Versluys, Birgitta A; Lindemans, Caroline A; Boelens, Jaap J; DeRisi, Joseph L; ,
Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 children's hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality (P = 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands (P = 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung-immune system-microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes.
PMID: 38783139
ISSN: 1546-170x
CID: 5655032
Longitudinal Lower Airway Microbial Signatures of Acute Cellular Rejection in Lung Transplantation
Natalini, Jake G; Wong, Kendrew K; Nelson, Nathaniel C; Wu, Benjamin G; Rudym, Darya; Lesko, Melissa B; Qayum, Seema; Lewis, Tyler C; Wong, Adrian; Chang, Stephanie H; Chan, Justin C Y; Geraci, Travis C; Li, Yonghua; Wang, Chan; Li, Huilin; Pamar, Prerna; Schnier, Joseph; Mahoney, Ian J; Malik, Tahir; Darawshy, Fares; Sulaiman, Imran; Kugler, Matthias C; Singh, Rajbir; Collazo, Destiny E; Chang, Miao; Patel, Shrey; Kyeremateng, Yaa; McCormick, Colin; Barnett, Clea R; Tsay, Jun-Chieh J; Brosnahan, Shari B; Singh, Shivani; Pass, Harvey I; Angel, Luis F; Segal, Leopoldo N
PMID: 38358857
ISSN: 1535-4970
CID: 5633542
Pathobiological signatures of dysbiotic lung injury in pediatric patients undergoing stem cell transplantation
Zinter, Matt S.; Dvorak, Christopher C.; Mayday, Madeline Y.; Reyes, Gustavo; Simon, Miriam R.; Pearce, Emma M.; Kim, Hanna; Shaw, Peter J.; Rowan, Courtney M.; Auletta, Jeffrey J.; Martin, Paul L.; Godder, Kamar; Duncan, Christine N.; Lalefar, Nahal R.; Kreml, Erin M.; Hume, Janet R.; Abdel-Azim, Hisham; Hurley, Caitlin; Cuvelier, Geoffrey D.E.; Keating, Amy K.; Qayed, Muna; Killinger, James S.; Fitzgerald, Julie C.; Hanna, Rabi; Mahadeo, Kris M.; Quigg, Troy C.; Satwani, Prakash; Castillo, Paul; Gertz, Shira J.; Moore, Theodore B.; Hanisch, Benjamin; Abdel-Mageed, Aly; Phelan, Rachel; Davis, Dereck B.; Hudspeth, Michelle P.; Yanik, Greg A.; Pulsipher, Michael A.; Sulaiman, Imran; Segal, Leopoldo N.; Versluys, Birgitta A.; Lindemans, Caroline A.; Boelens, Jaap J.; DeRisi, Joseph L.
Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 children"™s hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality (P = 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands (P = 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung"“immune system"“microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes.
SCOPUS:85193908971
ISSN: 1078-8956
CID: 5660632
Lower Airway Dysbiosis Augments Lung Inflammatory Injury in Mild-to-Moderate Chronic Obstructive Pulmonary Disease
Sulaiman, Imran; Wu, Benjamin G; Chung, Matthew; Isaacs, Bradley; Tsay, Jun-Chieh J; Holub, Meredith; Barnett, Clea R; Kwok, Benjamin; 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
PMID: 37677136
ISSN: 1535-4970
CID: 5606572
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.
PMCID:10632519
PMID: 37938580
ISSN: 2041-1723
CID: 5609852
Local and Systemic Antibody Response to SARS-CoV-2 Infection in Critically Ill COVID-19 Patients
Barnett, C.R.; Krolikowski, K.; Tsay, J.J.; Wu, B.G.; Li, Y.; Chang, M.; Kyeremateng, Y.; Brosnahan, S.; Singh, S.; Kocak, I.; Collazo, D.E.; Mukherjee, V.; Lubinsky, A.S.; Postelnicu, R.; Ghedin, E.; Chung, M.; Angel, L.F.; Sulaiman, I.; Duerr, R.; Schluger, R.; Rafeq, S.; Carpenito, J.; Bakker, J.; Amoroso, N.E.; Kaufman, D.A.; Pradhan, D.; Li, H.; Wang, C.; Silverman, G.; Segal, L.N.
ORIGINAL:0017185
ISSN: 1535-4970
CID: 5651662
Profiling the Functional Microbiome in Mild COPD
Isaacs, B.; Chung, M.; Wu, B.G.; Tsay, J.-C.; Barnett, C.R.; Kwok, B.; Kugler, M.C.; Natalini, J.G.; Singh, S.; Li, Y.; Schluger, R.; Carpenito, J.; Collazo, D.E.; Perez, L.; Kyeremateng, Y.; Chang, M.; Weiden, M.D.; Clemente, J.; Askenazi, M.; Jones, D.; Ghedin, E.; Segal, L.N.; Sulaiman, I.
ORIGINAL:0017183
ISSN: 1535-4970
CID: 5651642
Complexities of the Lower Airway Microbiome in Bronchiectasis and NTM Lung Disease
Singh, S.; Collazo, D.E.; Krolikowski, K.; Atandi, I.; Wong, K.; Erlandson, K.; Kwok, B.; Barnett, C.R.; Li, Y.; Chang, M.; Schluger, R.; Kocak, I.F.; Singh, R.; McCormick, C.; Kyeremateng, Y.; Darawshy, F.; Kugler, M.; Sulaiman, I.; Tsay, J.J.; Basavaraj, A.; Kamelhar, D.; Addrizzo-Harris, D.J.; Segal, L.N.; Wu, B.G.
ORIGINAL:0017181
ISSN: 1073-449x
CID: 5651622
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.
PMCID:9957952
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.
PMCID:9908925
PMID: 36755121
ISSN: 2045-2322
CID: 5426932