Segal Lab Research
Early Chronic Obstructive Pulmonary Disease (COPD)
Although lower airway colonization with pathogens has been well known to occur in advanced stage COPD, little is understood about the possible effects of dysbiosis of the lung microbiome in the pathogenesis of COPD. Our current projects seek to dissect the influence of the lung microbiome in the lower airway inflammatory tone that leads to airway injury and inflammation in early phases of this disease. Further, the potential contributions of lower airway dysbiosis to the susceptibility to pathogens is not known in this disease. Our research focuses on obtaining samples from smokers with and without COPD to perform extensive microbiome and host immune profile. In addition, we conduct in-vitro and in-vivo experiments on preclinical models to mechanistically evaluate how lower airway dysbiosis contributes to the pathogenesis of this disease.
Despite the declining prevalence of smoking in the U.S., lung cancer continues to be the leading cause of cancer deaths. Treatment of lung cancer with immunotherapy, such as PD-1 blockers, has become first line therapy for most non-small cell lung cancers but has variable effectiveness. It is still unclear what factors determine individuals’ response to immunotherapy. Our lab has demonstrated that lower airway microbiota signatures are associated with host immune tone and that there is a dysbiotic signature associated with upregulation of pro-cancer inflammatory pathways. Our investigations include the use of functional microbiomics and preclinical lung cancer models to uncover how lower airway dysbiosis contributes to the pathogenesis of lung cancer.
Lower airway infection remains one of the major causes of mortality all over the world. Lower airway infection may be a modifiable event with the discovery of the lower airway microbiome. The project studying pathogen susceptibility of the lower airway using metagenomic and single cell transcriptomics will identify unique mechanisms and pathways that may alter lower airway susceptibility to infection. The project utilizes animal models and human samples collected from subjects with lower airway infection. Exposure to anaerobic commensals and their metabolites from the upper airway may provide a key exposure for trained immunity to increase or decrease host susceptibility to infection.
Nontuberculous Mycobacteria and Bronchiectasis
The incidence of nontuberculous mycobacteria (NTM) and bronchiectasis has steadily been on the rise and surpasses that of Mycobacterium tuberculosis (Mtb) in the United States and other developed countries. The mechanisms that lead to increased susceptibility to this environmental mycobacterium in certain individuals are poorly delineated. The association with human genetic abnormalities is weak, thus suggesting that other environmental factors are likely important players. In addition, therapeutic approaches have high toxicity and limited efficacy. We have described how the lung microbiome of patients with this disease is diverse and almost never dominated by Mycobacterium. Our current research focus is on the effects of the lower airway microbiome (beyond the known pathogen) on the host immune phenotype as a tool to further explore the clinical phenotypes (for example radiology and FACED scores) that can be predictive of recalcitrant disease. We have also developed a murine model to uncover the mechanistic underpinnings of this heterogeneous disease.
Mycobacterium Tuberculosis (TB)
Mycobacterium tuberculosis remains the leading infectious disease in the world, claiming 1.5 million lives annually. The majority of individuals with latent tuberculosis remain symptom-free and non-infectious. However, among those individuals with latent TB, there is an approximately 12% lifetime risk of developing active TB. Preliminary studies indicate that the microbiome may have a role in the pathogenesis, and that treatment is likely to have an extensive impact on long-term human microbiome diversity. Through our collaboration with scientists in South Africa, we are interested in exploring changes in the gut and airway microbiome occurring in patients with tuberculosis before and during treatment for active tuberculosis that may better explain susceptibility to active disease and response to treatment.
Early mortality after lung transplantation is predominantly related to primary graft dysfunction (PGD), acute rejection, and pulmonary infections. Over time, declining survival rates are primarily attributed to a loss in graft function secondary to chronic lung allograft dysfunction (CLAD). The search for causes of CLAD in transplant recipients has been elusive. Early post-transplant complications such as severe PGD and acute rejection constitute important risk factors for the subsequent development of CLAD. Other clinical entities such as circulating donor-specific antibodies, gastroesophageal flux disease, and certain pulmonary infections including cytomegalovirus, Pseudomonas aeruginosa, Staphylococcus aureus, and Aspergillus are also associated with the development of CLAD. We are therefore conducting studies utilizing longitudinally collected lower airway, upper airway, and blood samples from lung transplant recipients to identify lower airway microbiota signatures associated with changes in host immune response, acute rejection, and CLAD.
Despite the homogenous nature of the pathogen, there is significant heterogeneity in the natural history of these critically ill COVID-19 patients, varying from patients requiring transient ventilatory support to prolonged mechanical ventilation and death. Our understanding of the determinants of different clinical outcomes among critically ill COVID-19 patients is very limited. During this pandemic, we employed our existing infrastructure to build a cohort with comprehensive detailed clinical data and ample biorepository of samples from critically ill COVID-19 patients. Our focus is on identifying microbial and host signatures associated with poor outcome
Sarcoidosis is a systemic granulomatous disease with a highly variable clinical course. The cause of sarcoidosis and its phenotypic heterogeneity remains unclear. Although microbial triggers have long been proposed, studies have focused on trying to identify microbial signatures associated with sarcoidosis diagnosis rather than those associated with its distinct phenotypes. In the lab we are evaluating whether microbial or host inflammatory signals could identify distinct endotypes that explain differences in sarcoidosis phenotype.
Venous Thromboembolic Disease
Venous thromboembolism (VTE), made up of deep vein thrombosis (DVT) and pulmonary embolism (PE), is an extremely common problem. Identifying patients at high risk for VTE is difficult and while the central doctrine behind the pathogenesis of VTE relies on Virchow’s triad (stasis, endothelial damage, and hypercoagulability) individuals’ cause for thrombosis can vary according to the subjects’ predisposing factors and thus, personalized prophylactic approaches are probably needed. Septic events, especially those of the lung such as pneumonia carry with it a higher rate of VTE and other hospitalizations. Our laboratory focuses on the use of different omic approaches to dissect signatures predictive of PE that will differ among patients with distinct risks factors.
Critical illness is a multiorgan system but often given its high correlation with acute respiratory distress syndrome (ARDS) carries a strong impact on the lungs. Our group studies critically ill patients’ lower airway and whole blood transcriptome (RNA sequencing) to help determine the interplay between the lung and body in ARDS. We focus on both acute and chronic outcomes after critical illness both within out ICU and after discharge.
Interstitial Lung Disease/Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease that is characterized by progressive scarring of the alveolar walls, carries a grim prognosis, and has limited treatment options. Scars are thought to arise due to aberrant signaling between chronically injured alveolar epithelium and mesenchymal cell populations, including myofibroblasts and fibroblasts. Our studies aim to address how signals that in the physiological context of lung development are orchestrated to control their differentiation become discordant in the pathological setting of IPF to create a vicious cycle of progressive fibrosis. We have focused on the role of developmental signaling pathways, which signal from epithelium to the mesenchyme, including Hedgehog (HH) and platelet-derived growth factor (PDGF) signaling, because they control fate of key developmental fibroblast populations, are aberrantly expressed in IPF and have fibrogenic properties, and can support both lung regenerative and fibrotic repair responses.
Lung Development/Bronchopulmonary Dysplasia
Bronchopulmonary dysplasia (BPD) is a serious chronic lung disease without targeted treatments, caused by perinatal lung injury that impairs formation and maturation of alveoli in premature infants. The pathobiology of BPD remains mostly unknown, but it is thought to be a result of injury-induced disruption of the coordinated signals between different cell types that are required for normal postnatal lung development. The rationale for our studies is that understanding of how such key developmental signaling pathways, such as HH and PDGF, control the coordination of different cells to correctly form alveoli in postnatal lung is needed for approaches to induce these cells to regenerate alveoli after perinatal injury and in BPD.