Faculty Bibliography
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American journal of respiratory cell & molecular biology. 2023:68(5):523-536.DOI: 10.1165/rcmb.2022-0269OC
Hedgehog and PDGF Signaling Intersect During Postnatal Lung Development
Normal lung development critically depends on Hedgehog (HH) and Platelet-derived growth factor (PDGF) signaling, which coordinate mesenchymal differentiation and proliferation. PDGF signaling is required for postnatal alveolar septum formation by myofibroblasts. Recently, we demonstrated a requirement for HH in postnatal lung development involving alveolar myofibroblast differentiation. Given shared features of HH and PDGF signaling and their impact/convergence on this key cell type, we sought to clarify their relationship during murine postnatal lung development. Timed experiments revealed that HH inhibition phenocopies the key lung myofibroblast phenotypes of Pdgfa and Pdgfra knockouts during secondary alveolar septation. Utilizing a dual signaling reporter, Gli1IZ;PdgfraEGFP
PMID: 36693140
ISSN: 1535-4989
CID: 5419542
American journal of respiratory & critical care medicine. 2022:206(7):806-808.DOI: 10.1164/rccm.202206-1074ED
Untangling Lower Airway Dysbiosis in Critically-Ill COVID-19 Patients
PMID: 35696343
ISSN: 1535-4970
CID: 5282522
ACE2-containing defensosomes serve as decoys to inhibit SARS-CoV-2 infection
Extracellular vesicles of endosomal origin, exosomes, mediate intercellular communication by transporting substrates with a variety of functions related to tissue homeostasis and disease. Their diagnostic and therapeutic potential has been recognized for diseases such as cancer in which signaling defects are prominent. However, it is unclear to what extent exosomes and their cargo inform the progression of infectious diseases. We recently defined a subset of exosomes termed defensosomes that are mobilized during bacterial infection in a manner dependent on autophagy proteins. Through incorporating protein receptors on their surface, defensosomes mediated host defense by binding and inhibiting pore-forming toxins secreted by bacterial pathogens. Given this capacity to serve as decoys that interfere with surface protein interactions, we investigated the role of defensosomes during infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of Coronavirus Disease 2019 (COVID-19). Consistent with a protective function, exosomes containing high levels of the viral receptor ACE2 in bronchoalveolar lavage fluid (BALF) from critically ill COVID-19 patients was associated with reduced intensive care unit (ICU) and hospitalization times. We found ACE2+ exosomes were induced by SARS-CoV-2 infection and activation of viral sensors in cell culture, which required the autophagy protein ATG16L1, defining these as defensosomes. We further demonstrate that ACE2+ defensosomes directly bind and block viral entry. These findings suggest that defensosomes may contribute to the antiviral response against SARS-CoV-2 and expand our knowledge on the regulation and effects of extracellular vesicles during infection.
PMID: 36099266
ISSN: 1545-7885
CID: 5335192
A clinicians' review of the respiratory microbiome
The respiratory microbiome and its impact in health and disease is now well characterised. With the development of next-generation sequencing and the use of other techniques such as metabolomics, the functional impact of microorganisms in different host environments can be elucidated. It is now clear that the respiratory microbiome plays an important role in respiratory disease. In some diseases, such as bronchiectasis, examination of the microbiome can even be used to identify patients at higher risk of poor outcomes. Furthermore, the microbiome can aid in phenotyping. Finally, development of multi-omic analysis has revealed interactions between the host and microbiome in some conditions. This review, although not exhaustive, aims to outline how the microbiome is investigated, the healthy respiratory microbiome and its role in respiratory disease.
PMCID:9584600
PMID: 36338247
ISSN: 1810-6838
CID: 5357002
Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome
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
Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome
Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.
PMCID:8010736
PMID: 33791687
ISSN: n/a
CID: 4830952
Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome
Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.
PMCID:7924286
PMID: 33655261
ISSN: n/a
CID: 4801472
Evaluation of the Lower Airway Microbiota in Patients with Severe SARS-CoV2 [Meeting Abstract]
ISI:000685468900221
ISSN: 1073-449x
CID: 5230292
The presence of Oxalobacter formigenes in the microbiome of healthy young adults
Oxalobacter formigenes, a member of the human colonic microbiota that plays a major role in net colonic oxalate transport and secretion, is protective against formation of calcium oxalate kidney stones. We now describe the prevalence, relative abundance and stability of O. formigenes in healthy young adults in the United States, as revealed by Human Microbiome Project (HMP) data from fecal samples from 242 healthy young adults who had 1-3 study visits. Samples underwent whole-genomic shotgun (WGS) sequencing, and/or 16S rRNA sequencing. Three datasets available from the processed sequence data were studied: WGS metagenomic analysis by alignment to reference genomes (HMSCP) or using MetaPhlAn, or QIIME analysis of the V1-3 or V3-5 16S sequences. O. formigenes was detected in fecal samples using both the WGS and 16S rRNA data. Analysis of the WGS dataset, using HMSCP, showed that 29 (31%) of 94 subjects were O. formigenes-positive while the V1-3 and V3-5 analyses were less sensitive for O. formigenes detection. When present, O. formigenes relative abundance varied over 3 log10, and was normally distributed. For 66 samples studied by all three methods, all assays agreed in 58 (88%). Of 14 subjects who were O. formigenes-positive at baseline, 13 (93%) were positive on follow-up visit, indicating the stability of colonization. O. formigenes appears to be stably present in fewer than half of healthy young USA adults and is most sensitively detected by WGS.
PMCID:4747808
PMID: 26292041
ISSN: 1527-3792
CID: 1732452
Acute gastritis with hypochlorhydria: report of 35 cases with long term follow up
BACKGROUND: Between 1976 and 1987, 35 cases of acute gastritis with hypochlorhydria (AGH) were seen in our research laboratory. The aims of this study were to determine the natural history of AGH and the role of Helicobacter pylori in its pathogenesis. METHODS: Archived serum and gastric biopsy samples obtained from AGH subjects were examined for evidence of H pylori colonisation. Twenty eight of 33 (85%) surviving AGH subjects returned a mean of 12 years after AGH for follow up studies, including determination of H pylori antibodies, basal and peak acid output, endoscopy, and gastric biopsies. A matched control group underwent the same studies. RESULTS: Archived material provided strong evidence of new H pylori acquisition in a total of 14 subjects within two months, in 18 within four months, and in 22 within 12 months of recognition of AGH. Prevalence of H pylori colonisation at follow up was 82% (23 of 28) in AGH subjects, significantly (p<0.05) higher than in matched controls (29%). Basal and peak acid output returned to pre-AGH levels in all but two subjects. CONCLUSIONS: One of several possible initial manifestations of H pylori acquisition in adults may be AGH. While H pylori colonisation usually persists, hypochlorhydria resolves in most subjects
PMCID:1728062
PMID: 10986205
ISSN: 0017-5749
CID: 19040
