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Anti-Mycobacterials and Micro-Aspiration Drive Lower Airway Dysbiosis in NTM Bronchiectasis [Meeting Abstract]

Singh, S.; Hoque, A.; Sulaiman, I.; Li, Y.; Wu, B.; Chang, M.; Kyeremateng, Y.; Collazo, D. E.; Kamelhar, D.; Addrizzo-Harris, D. J.; Segal, L. N.
ISSN: 1073-449x
CID: 5238232

Chronic Lower Airway Dysbiosis with Human Oral Commensals Leads to Both Increased IL-17A and Immune Exhaustion Tone in the Lower Airways [Meeting Abstract]

Chang, M.; Kyeremateng, Y.; Collazo, D.; Kocak, I.; Singh, S.; Li, Y.; Tsay, J.; Segal, L. N.; Wu, B. G.
ISSN: 1073-449x
CID: 5238222

Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome

Sulaiman, Imran; Chung, Matthew; Angel, Luis; Tsay, Jun-Chieh J; Wu, Benjamin G; Yeung, Stephen T; Krolikowski, Kelsey; Li, Yonghua; Duerr, Ralf; Schluger, Rosemary; Thannickal, Sara A; Koide, Akiko; Rafeq, Samaan; Barnett, Clea; Postelnicu, Radu; Wang, Chang; Banakis, Stephanie; Pérez-Pérez, Lizzette; Shen, Guomiao; Jour, George; Meyn, Peter; Carpenito, Joseph; Liu, Xiuxiu; Ji, Kun; Collazo, Destiny; Labarbiera, Anthony; Amoroso, Nancy; Brosnahan, Shari; Mukherjee, Vikramjit; Kaufman, David; Bakker, Jan; Lubinsky, Anthony; Pradhan, Deepak; Sterman, Daniel H; Weiden, Michael; Heguy, Adriana; Evans, Laura; Uyeki, Timothy M; Clemente, Jose C; de Wit, Emmie; Schmidt, Ann Marie; Shopsin, Bo; Desvignes, Ludovic; Wang, Chan; Li, Huilin; Zhang, Bin; Forst, Christian V; Koide, Shohei; Stapleford, Kenneth A; Khanna, Kamal M; Ghedin, Elodie; Segal, Leopoldo N
Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2.
PMID: 34465900
ISSN: 2058-5276
CID: 4998422

Functional lower airways genomic profiling of the microbiome to capture active microbial metabolism

Sulaiman, Imran; Wu, Benjamin G; Li, Yonghua; Tsay, Jun-Chieh; Sauthoff, Maya; Scott, Adrienne S; Ji, Kun; Koralov, Sergei B; Weiden, Michael; Clemente, Jose; Jones, Drew; Huang, Yvonne J; Stringer, Kathleen A; Zhang, Lingdi; Geber, Adam; Banakis, Stephanie; Tipton, Laura; Ghedin, Elodie; Segal, Leopoldo N
RATIONALE/BACKGROUND:Microbiome studies of the lower airway based on bacterial 16S rRNA gene sequencing assess microbial community structure but can only infer functional characteristics. Microbial products, such as short chain fatty acids (SCFAs), in the lower airways have significant impact on the host's immune tone. Thus, functional approaches to the analyses of the microbiome are necessary. METHODS:Here we used upper and lower airway samples from a research bronchoscopy smoker cohort. In addition, we validated our results in an experimental mouse model. MEASUREMENTS/METHODS:We extended our microbiota characterisation beyond 16S rRNA gene sequencing with the use of whole genome (WGS) and RNA metatranscriptome sequencing. Short chain fatty acids (SCFA) were also measured in lower airway samples and correlated with each of the sequencing datasets. In the mouse model, 16S rRNA gene and RNA metatranscriptome sequencing were performed. MAIN RESULTS/RESULTS:Functional evaluations of the lower airway microbiota using inferred metagenome, WGS and metatranscriptome were dissimilar. Comparison with measured levels of SCFAs shows that the inferred metagenome from the 16S rRNA gene sequencing data was poorly correlated, while better correlations were noted when SCFAs levels were compared with WGS and metatranscriptome. Modelling lower airway aspiration with oral commensals in a mouse model showed that the metatranscriptome most efficiently captures transient active microbial metabolism, which was overestimated by 16S rRNA gene sequencing. CONCLUSIONS:Functional characterisation of the lower airway microbiota through metatranscriptome identify metabolically active organisms capable of producing metabolites with immunomodulatory capacity such as SCFAs.
PMID: 33446604
ISSN: 1399-3003
CID: 4747282

Anaerobe-enriched gut microbiota predicts pro-inflammatory responses in pulmonary tuberculosis

Naidoo, Charissa C; Nyawo, Georgina R; Sulaiman, Imran; Wu, Benjamin G; Turner, Carolin T; Bu, Kevin; Palmer, Zaida; Li, Yonghua; Reeve, Byron W P; Moodley, Suventha; Jackson, Jennifer G; Limberis, Jason; Diacon, Andreas H; van Helden, Paul D; Clemente, Jose C; Warren, Robin M; Noursadeghi, Mahdad; Segal, Leopoldo N; Theron, Grant
BACKGROUND:The relationship between tuberculosis (TB), one of the leading infectious causes of death worldwide, and the microbiome, which is critical for health, is poorly understood. METHODS:To identify potential microbiome-host interactions, profiling of the oral, sputum and stool microbiota [n = 58 cases, n = 47 culture-negative symptomatic controls (SCs)] and whole blood transcriptome were done in pre-treatment presumptive pulmonary TB patients. This was a cross-sectional study. Microbiota were also characterised in close contacts of cases (CCCs, n = 73) and close contacts of SCs (CCSCs, n = 82) without active TB. FINDINGS/RESULTS:Cases and SCs each had similar α- and β-diversities in oral washes and sputum, however, β-diversity differed in stool (PERMANOVA p = 0•035). Cases were enriched with anaerobes in oral washes, sputum (Paludibacter, Lautropia in both) and stool (Erysipelotrichaceae, Blautia, Anaerostipes) and their stools enriched in microbial genes annotated as amino acid and carbohydrate metabolic pathways. In pairwise comparisons with their CCCs, cases had Megasphaera-enriched oral and sputum microbiota and Bifidobacterium-, Roseburia-, and Dorea-depleted stools. Compared to their CCSCs, SCs had reduced α-diversities and many differential taxa per specimen type. Cases differed transcriptionally from SCs in peripheral blood (PERMANOVA p = 0•001). A co-occurrence network analysis showed stool taxa, Erysipelotrichaceae and Blautia, to negatively co-correlate with enriched "death receptor" and "EIF2 signalling" pathways whereas Anaerostipes positively correlated with enriched "interferon signalling", "Nur77 signalling" and "inflammasome" pathways; all of which are host pathways associated with disease severity. In contrast, none of the taxa enriched in SCs correlated with host pathways. INTERPRETATION/CONCLUSIONS:TB-specific microbial relationships were identified in oral washes, induced sputum, and stool from cases before the confounding effects of antibiotics. Specific anaerobes in cases' stool predict upregulation of pro-inflammatory immunological pathways, supporting the gut microbiota's role in TB. FUNDING/BACKGROUND:European & Developing Countries Clinical Trials Partnership, South African-Medical Research Council, National Institute of Allergy and Infectious Diseases.
PMID: 33975252
ISSN: 2352-3964
CID: 4878352

Episodic Aspiration with Oral Commensals Induces a MyD88-dependent, Pulmonary Th17 Response that Mitigates Susceptibility to Streptococcus pneumoniae

Wu, Benjamin G; Sulaiman, Imran; Tsay, Jun-Chieh J; Perez, Luisanny; Franca, Brendan; Li, Yonghua; Wang, Jing; Gonzalez, Amber N; El-Ashmawy, Mariam; Carpenito, Joseph; Olsen, Evan; Sauthoff, Maya; Yie, Kevin; Liu, Xiuxiu; Shen, Nan; Clemente, Jose C; Kapoor, Bianca; Zangari, Tonia; Mezzano, Valeria; Loomis, Cynthia; Weiden, Michael D; Koralov, Sergei; D'Armiento, Jeanine; Ahuja, Sunil K; Wu, Xue-Ru; Weiser, Jeffrey N; Segal, Leopoldo N
Rationale Cross-sectional human data suggest that enrichment of oral anaerobic bacteria in the lung is associated with increased Th17 inflammatory phenotype. In this study we evaluated the microbial and host immune response dynamics after aspiration with a oral commensals using a preclinical mouse model. Methods Aspiration with a mixture of human oral commensals (MOC; Prevotella melaninogenica, Veillonella parvula, and Streptococcus mitis) was modeled in mice followed by variable time of sacrifice. Genetic background of mice included WT, MyD88 knock out and STAT3C. Measurements 16S rRNA gene sequencing characterized changes in microbiota. Flow cytometry, cytokine measurement via Luminex and RNA host transcriptome sequencing was used to characterize host immune phenotype. Main Results While MOC aspiration correlated with lower airway dysbiosis that resolved within five days, it induced an extended inflammatory response associated with IL17-producing T-cells lasting at least 14 days. MyD88 expression was required for the IL-17 response to MOC aspiration, but not for T-cell activation or IFN-γ expression. MOC aspiration prior to a respiratory challenge with S. pneumoniae led to a decreased in host's susceptibility to this pathogen. Conclusions Thus, in otherwise healthy mice, a single aspiration event with oral commensals are rapidly cleared from the lower airways, but induce a prolonged Th17 response that secondarily decreased susceptibility to respiratory pathogens. Translationally, these data implicate an immuno-protective role of episodic microaspiration of oral microbes in the regulation of the lung immune phenotype and mitigation of host susceptibility to infection with lower airway pathogens.
PMID: 33166473
ISSN: 1535-4970
CID: 4664852

d-dimer and Death in Critically Ill Patients With Coronavirus Disease 2019

Short, Samuel A P; Gupta, Shruti; Brenner, Samantha K; Hayek, Salim S; Srivastava, Anand; Shaefi, Shahzad; Singh, Harkarandeep; Wu, Benjamin; Bagchi, Aranya; Al-Samkari, Hanny; Dy, Rajany; Wilkinson, Katherine; Zakai, Neil A; Leaf, David E
OBJECTIVES:Hypercoagulability may be a key mechanism for acute organ injury and death in patients with severe coronavirus disease 2019, but the relationship between elevated plasma levels of d-dimer, a biomarker of coagulation activation, and mortality has not been rigorously studied. We examined the independent association between d-dimer and death in critically ill patients with coronavirus disease 2019. DESIGN:Multicenter cohort study. SETTING:ICUs at 68 hospitals across the United States. PATIENTS:Critically ill adults with coronavirus disease 2019 admitted to ICUs between March 4, 2020, and May 25, 2020, with a measured d-dimer concentration on ICU day 1 or 2. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:The primary exposure was the highest normalized d-dimer level (assessed in four categories: < 2×, 2-3.9×, 4-7.9×, and ≥ 8× the upper limit of normal) on ICU day 1 or 2. The primary endpoint was 28-day mortality. Multivariable logistic regression was used to adjust for confounders. Among 3,418 patients (63.1% male; median age 62 yr [interquartile range, 52-71 yr]), 3,352 (93.6%) had a d-dimer concentration above the upper limit of normal. A total of 1,180 patients (34.5%) died within 28 days. Patients in the highest compared with lowest d-dimer category had a 3.11-fold higher odds of death (95% CI, 2.56-3.77) in univariate analyses, decreasing to a 1.81-fold increased odds of death (95% CI, 1.43-2.28) after multivariable adjustment for demographics, comorbidities, and illness severity. Further adjustment for therapeutic anticoagulation did not meaningfully attenuate this relationship (odds ratio, 1.73; 95% CI, 1.36-2.19). CONCLUSIONS:In a large multicenter cohort study of critically ill patients with coronavirus disease 2019, higher d-dimer levels were independently associated with a greater risk of death.
PMID: 33591017
ISSN: 1530-0293
CID: 4861902

The effect of lower airway dysbiosis on pd-1 therapy in lung cancer [Meeting Abstract]

Tsay, J J; Wu, B; Pillai, R; Sulaiman, I; Carpenito, J; Li, Y; Segal, L N
Rational Recent investigations support that the gut microbiota influences anti-PD-1 cancer immunotherapy. Lower airway dysbiosis with enrichment with oral commensals are associated with lung cancer. Recently we had shown, in both a prospective human cohort and preclinical mice model, that lung dysbiotic signatures were associated with clinical lung cancer prognosis and progression. To further understand the role of lung dysbiosis in lung cancer, we examined the role of PD-1 expression and anti- PD treatment in a lung cancer and lung dysbiotic model. Method KrasLSL-G12D/+;p53fl/fl Non-small cell Lung Cancer mice (KP) were challenged with an oral commensal, Veillonella parvula, through intra-tracheal inoculation and exposed to immune inhibition (anti- PD-1). Measurements included tumor burden and lower airway inflammatory markers (PD-1 expression and neutrophils) by FACS. Results In a preclinical lung cancer model, inoculation with Veillonella parvula, a marker taxon for the dysbiotic signature found in humans, led to: 1) decrease survival with increase tumor burden; 2) dysbiosis with oral commensal is associated with elevated level of PD-1 expression and neutrophils level compared to control. With exposure to PD-1 inhibition we observe a reverse of tumor growth (at day 7); there was significant decrease in tumor growth compared with Isotype-control (p=0.030, day7-14) and observed that PD-1+ level (p=0.0007) and Neutrophil level (p=0.0027) were lower as well. Discussion Our study suggests that lower airway dysbiosis induced by microaspiration of oral commensals may affect lung carcinogenesis due to increase in inflammatory markers and increase in the checkpoint inhibitor tone in the lower airways that may lead to suboptimal immune surveillance. These effects of lower airway dysbiosis can be partially blunted by PD-1 blockade. These data supports that treatment in lung cancer may be influenced by lower airway dysbiosis and dynamic changes in the microbial-host interaction in the lower airways
ISSN: 1535-4970
CID: 4915732

Lower airway microbiota predicts malignancy recurrence of surgically resected early-stage lung cancer [Meeting Abstract]

Kwok, B; Tsay, J J; Sulaiman, I; Wu, B G; Li, Y; Pass, H I; Segal, L N
Rationale: In early-stage non-small cell lung cancer (NSCLC), surgery is curative in about 70% of cases. Unfortunately, there are no useful biomarkers that predict recurrence. We have previously shown that lower airway dysbiosis due to enrichment with oral commensals in patients with different stages of lung cancer is associated with activation of airway transcriptomic signatures involved in inflammation, oncogenesis, tumor burden, and prognosis. Here, we investigated the lower airway microbiota of subjects with early-stage NSCLC undergoing surgical resection as a biomarker that predicts tumor recurrence.
Method(s): 150 subjects with stage I NSCLC who underwent primary surgical resection were followed for up to 10 years for cancer recurrence. Microbiota of the tumor and adjacent unaffected lung tissue was examined by 16S rRNA gene sequencing while host transcriptome was characterized by RNA sequencing.
Result(s): Of the 150 subjects, 44 had recurrence of malignancy (in the forms of locoregional disease, metastatic disease, and second primary NSCLC). Comparison of microbial community composition based on Bray Curtis dissimilarity index showed significant differences between tumor and lung and, within those different sample types, between recurrence and no recurrence. In tumor samples, recurrence was associated with enrichment with Methylophilaceae, while in adjacent lung tissue there was a significant enrichment with Methylophilaceae and Vellonella. In lung samples, Flavobacterium, a common background contaminant, was negatively associated with recurrence. Shannon's diversity (H) was statistically different between tumor and adjacent tissue in subjects without recurrence; H was not statistically different between tumor and adjacent tissue in those with recurrence. Transcriptome data by DESseq2 analyses identified few transcripts in tumors associated with recurrence (272 up regulated, 91 downregulated, FDR=0.2), many more were identified in healthy lung (579 up regulated, 216 downregulated, FDR=0.2). Ingenuity pathway analysis (IPA) found recurrence was associated with upregulation of many cancer associated pathways, IL-17 and PD-1, PD-L1 pathways.
Conclusion(s): In this investigation we identified lower airway microbiota signatures and host immune signatures present at time of surgical resection of early-stage NSLCL that predict tumor recurrence. Further investigation to dissect possible causal associations of microbial host interactions leading to recurrence is warranted
ISSN: 1535-4970
CID: 4915432

Lower airway microbial signatures in early copd [Meeting Abstract]

Holub, M; Tsay, J; Wu, B; Sulaiman, I; Schluger, R; Li, Y; Carpenito, J; Koralov, S B; Clemente, J; Segal, L N
Rationale: Chronic airway colonization and recurrent infections are common in advanced stage chronic obstructive pulmonary disease (COPD). However, changes in the lung microbiota in early stages of this disease remain unclear. Here, we characterized the upper and lower airway microbiota of patients with early stage COPD and smoker controls.
Method(s): Upper and lower airway samples (plus appropriate environmental and technical controls) were obtained from patients with GOLD 1-2 COPD (n = 26) and smoker controls (n = 31). Bacterial load was measured with droplet digital PCR while microbiota profiling was performed using 16S rRNA gene sequencing. Data was analyzed using QIIME, Phyloseq, Vegan and DESeq. Parallel RNA metatranscriptome sequencing and host Transcriptome approach were just completed and data is becoming available.
Result(s): Characterization of the lower airway microbial communities with 16S rRNA gene sequencing showed that compared to smoker controls, COPD patients exhibited lower alpha Shannon diversity (Fig.1a, p = 0.0037). Beta diversity analysis based on Bray Curtis Dissimilarity index showed that the composition of the microbial communities in the lower airway samples were clearly distinct from background and upper airway as a whole. Some samples overlapped with both of those areas suggesting that for some subjects their lower airway microbiota was enriched with taxa commonly found in the oral cavity. We then evaluated for differentially enriched taxa in BAL samples using DESeq. The lower airway microbiota of subjects with COPD was enriched with oral commensals such as Veillonella, Prevotella (Fig 1c). Comparison of bacterial load based on bacterial composition was performed based on cluster determination of lower airway samples enriched with oral commensals (SPT for supraglottic predominant taxa) or enriched with background taxa (BPT for background predominant taxa). The bacterial load of lower airway samples categorized as SPT was one log higher than those categorized as BPT among the COPD group but not among the smoker controls (Fig.1d, p < 0.001).
Conclusion(s): Our results suggest that lower airway exposure to oral commensals occurs more frequently among subjects with COPD. Further investigation with functional microbiome approaches such as metatranscriptomics are warranted. This may be of importance given significant data showing that these taxa may contribute to an increase in lower airway inflammatory tone (especially in the Th17 pathway) that may lead to airway/parenchymal inflammatory damage and/or affect treatment response and clinical outcome in this disease
ISSN: 1535-4970
CID: 4915602