Coronavirus Update:What patients and families need to know

The Children's National Research Institute

Airway and Lung Diseases

The Center for Genetic Medicine Research's Airway Biology research group focuses on the "united airway" concept that epithelium and epithelial responses in the respiratory tract are similar and interrelated and that complex interactions between the epithelium and mesenchyme mediate lung development and inflammatory airway diseases. This year saw the publication of key findings advancing clinical care and major new grants ($3 million), including the renewal of the NHLBI-funded K12 (career development) Program in Omics of Pediatric Lung Diseases in DC and the recruitment of two K12 scholars, whose research focuses on the genomics of microorganisms in the lung. The 18 faculty members of the Airway Biology group, led by internationally recognized leaders (Robert J. Freishtat, M.D., M.P.H., and Diego Preciado, M.D., Ph.D.), who worked alongside investigators from the Center for Translational Research, the Sheikh Zayed Institute (SZI), private industry and other Genetic Medicine scientists. The team studies asthma, cystic fibrosis (CF), otitis media (OM), chronic rhinosinusitis (CRS), lung complications of sepsis and neonatal and infant respiratory disorders.

The Cell Culture Core, a key asset in Children’s National Hospital fight to treat airway and lung diseases, assists the respiratory biology research community at-large. The core supports studies in respiratory epithelial biology and trains junior faculty, fellows and students. Notably, recently they have incorporated the use of conditionally reprogrammed cell (CRC) technology to enhance cell growth and lifespan of nasal and bronchial primary cells from infants and young children. This milestone has greatly advanced the core’s ability to perform translational studies for a myriad of respiratory disorders in all ages.

Asthma in the United States is considerably more prevalent and severe than 40 years ago, yet the reasons for this are not clear. It remains one of the most significant childhood illnesses, disproportionately affecting urban youth, especially African Americans, who have among the highest asthma-related morbidity and mortality rates of any U.S. racial/ethnic group. The asthma team brings to bear patient-oriented and data-driven research to identify strategies to reduce the health disparities experienced by disadvantaged, urban and minority youth with asthma.
The airway biology team uses translational and multidisciplinary approaches to asthma research. The AsthMaP2® Project, led by Robert Freishtat, M.D., M.P.H., and funded by the National Institute on Minority Health and Health Disparities (NIMHD) is the basis for this research. Dinesh Pillai, M.D., and Dr. Freishtat lead efforts to mine the data-rich AsthMaP2® Project to gain insights into asthma. In addition, the AsthMaP2® Project serves as a central resource for the asthma studies in the center. An example of this is a collaboration between Dr. Freishtat and Marcos Perez-Losada, Ph.D., and the Computational Biology Institute at George Washington University (GW) using a new statistical framework (PathoScope) to accurately and quickly analyze airway DNA/RNA sequences to study the contribution of the microbiome to asthma and lung infections.
Asthma and Obesity: With rates of asthma and obesity increasing, it is critical to identify mechanisms by which obesity impacts asthma. The two epidemics disproportionately affect minority disadvantaged children, many of whom live in the inner city. The District of Columbia ranks third nationally in childhood obesity and has one of the highest asthma prevalence rates in the country. Obesity has been associated with increased asthma symptoms and poor response to asthma therapy. A multidisciplinary team led by Dr. Freishtat and Evan Nadler, M.D., (Sheikh Zayed Institute) continues to lead the field in the study of how excess fat tissue in obese patients drives abnormal processes in other organs like the lungs
Refractory Asthma: Dr. Pillai developed Children’s National's first Severe Asthma Clinic for high-risk children identified by their frequent visits to the emergency department and hospital admissions for therapy-resistant asthma. This valuable clinical resource aims to turn research into new treatments for therapy-resistant asthma.
Many of the pediatric respiratory tract diseases the team studies (asthma, CF, chronic rhinosinusitis CRS and otitis media (OM)) are typically characterized by mucus hypersecretion resulting from bacterial and viral infection and/or inflammatory responses that are somewhat specific to each disease. MUC5AC and MUC5B are the major secretory mucins in the respiratory tract. MUC5AC is expressed in goblet cells in airway epithelium and thus is poised to be one of the first innate immune responders to infection and inflammation. MUC5B, typically restricted to submucosal glands, can be overexpressed in lung diseases. Diego Preciado, M.D., Ph.D., and Maria Peña, M.D., reported that MUC5B is also the predominant mucin in CRS secretions. Dr. Preciado continues functional studies of upregulation of MUC5B mucin by bacteria and cytokines.
Cystic Fibrosis (CF): Cystic fibrosis, a recessive genetic disease, is the most prevalent orphan disease in the U.S. Patient morbidity and mortality are mainly due to lung disease. Andrea Hahn, M.D., and Robert J. Freishtat, M.D., M.P.H., are studying changes in the lung microbiome in cystic fibrosis children receiving antibiotic therapy. Preliminary data suggest that suboptimal antibiotic therapy against a cultured pathogen preferentially targets commensal microbes, leading to a further dominance of the pathogenic organism. The lab’s data also suggest that suboptimal antibiotic therapy is associated with decreased recovery of lung function following a bacterial lung infection.
Respiratory viruses: Rhinovirus and respiratory syncytial virus (RSV) are the most common cause of respiratory infections in children. Drs. Nino and Freishtat are investigating the mechanisms of disease of these respiratory viruses in infants and young children. In a recently published paper, the team identified that microRNA (miR)-155, a potent driver of interferon TH1 responses is part of the host defense response against rhinovirus. This complements prior observations in which the master TH2 cytokine, Thymic Stromal Lymphopoietin (TSLP), is associated with rhinovirus infections in infants. Dr. Freishtat also has recently identified that infants with rhinovirus and RSV infections have different nasal airway microRNA profiles associated with NFκB signaling. Ongoing work includes efforts to better study viral respiratory illnesses in young children using new clinical scores and novel lung imaging being developed in collaboration with the Quantitative Imaging/Bioengineering Initiative in the Sheikh Zayed Institute.
Investigations on the airway microbiome are steadily increasing the team’s understanding of the balance between pathogenic and protective organisms in a variety of disease processes. Drs. Perez, Perez-Losada, Nino and Hahn use Next-Gen sequencing to define the microbiome of patients with CF and acute rhinovirus infection. Along with Dr. Pillai they determine microbial populations in bronchiolar lavages from CF patients. Drs. Nino, Perez, Hahn and Perez-Losada have characterized the microbiome changes during natural rhinovirus infection in children born severely premature relative to children born full term.
Dr. Nino is investigating the pathobiology of respiratory disorders in newborns and young children, the number one cause of hospitalization and mortality in this vulnerable age group. There is a particular interest in understanding why babies born premature are highly susceptible to respiratory disorders. To address this question, the lab employs a variety of state-of-the-art techniques for respiratory phenotyping including age-appropriate multi-language scales and computer-based analysis of lung imaging and neonatal bedside monitors. The team has already identified that premature infants have autonomic dysfunction leading to acute life-threatening events and airway immune dysregulation (TH2-biased responses) against respiratory viruses causing recurrent hospitalizations. The team also investigating the developmental biology of the respiratory epithelium in human babies using a novel cellular model developed in the lab with conditional reprogramming cell technology to life-extend airway epithelial cells derived from newborns and infants born full-term and premature.
- Gustavo Nino, M.D., M.S.H.S.
Dr. Freishtat leads efforts on behalf of NIH-funded multicenter studies of genetic changes in overwhelming infections (sepsis) in children and is developing a new treatment for the complications of sepsis targeting a blood platelet protein. In collaboration with the neonatal intensive care unit and the Division of Materno-Fetal Medicine, Dr. Nino investigated the presence of nasal molecular as well as physiological biomarkers of respiratory disease in newborns and prematurely born infants. In a recent publication, the team identified non-invasive markers of autonomic dysfunction by cardiorespiratory monitoring that may lead to the prevention of respiratory-related hospitalizations in this vulnerable patient population.
- Robert J. Freishtat, M.D., M.P.H.
- Gustavo Nino, M.D., M.S.H.S.
Jyoti K. Jaiswal, Ph.D., and Anamaris M Colberg-Poley, Ph.D., study how the human cytomegalovirus (HCMV) reprograms host cell functions to facilitate viral growth and survival. HCMV infection targets a newly characterized sub-organelle, mitochondria-associated membranes (MAM). The MAM is an endoplasmic reticulum (ER) subdomain that contacts mitochondria and allows for inter-organelle crosstalk. The MAM plays a critical role in ER calcium (Ca2+) signaling to mitochondria (needed for cell metabolism), ER stress responses, innate immunity and programmed cell death.
Work by this group has previously identified that a viral protein called viral mitochondria-localized inhibitor of apoptosis (vMIA) which localizes prominently to the MAM and Mitochondria, and is required for the anti-apoptotic role of this protein. Using high-resolution fluorescence microscopy the group studies the mechanisms underlying vMIA trafficking. Using superresolution microscopy, they have found that the viral protein vMIA is organized in nanometric clusters at the outer mitochondrial membrane (OMM), similar to some of the other host mitochondrial proteins, including the translocase of the outer mitochondrial membrane (TOM) and voltage-dependent anion channel (VDAC). Work by the graduate student Mansi Mehta involving genetic and pharmacological inhibition of TOM complex, has helped investigate the requirement of this complex in incorporation of this membrane-anchored protein into the outer mitochondrial membrane. These studies are providing insight into a novel pathway that the virus may have adopted to target the host cell mitochondria and thus protect this protein from the host machinery to keep this protein from localizing to the mitochondria.
- Jyoti K. Jaiswal, Ph.D.
Linda Leatherbury, M.D., (Cardiology) and Iman Sami, M.D., (Pulmonary Medicine) have started a "Ciliary Dysfunction in Congenital Heart Disease and Suspected Primary Ciliary Dyskinesia" multidisciplinary clinic for research protocol patients. The team and Anastassios Koumbourlis, M.D., M.P.H., (Pulmonary Medicine) are co-investigators with Cecilia Lo, Ph.D., (University of Pittsburgh) on a grant from the Department of Defense (DOD) to study pulmonary function in children with congenital heart diseases.
- Linda Leatherbury, M.D.
- Iman Sami, M.D.

Coronavirus Update:What patients and families need to know

The Children's National Research Institute

Airway and Lung Diseases

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