Respiratory Syncytial Virus (RSV) Pathogenesis, Reverse Genetics, and Vaccinology
RSV is the leading cause of bronchiolitis, viral pneumonia, and viral death in infants. RSV is the leading cause of respiratory failure and mechanical ventilation in infants. There is no RSV vaccine in use and no widely available therapies. RSV is not only a scourge of infancy but also a major cause of asthma exacerbations in children and adults, and a major cause of pneumonia in the elderly.
Airway mucus is a hallmark feature of RSV lower respiratory tract infection. Mucus, necrotic epithelial cell debris, and inflammatory cells obstruct the airways, leading to characteristic wheezing and respiratory failure in severe cases.
We identified and derived strains of RSV that exhibit differential disease phenotypes in mice. Some RSV strains induce high levels of the cytokine IL-13, airway mucus, severe histopathology, and pulmonary obstruction, whereas other strains induce a more protective TH1-type response.
The primary focus of my laboratory is to define mechanisms of RSV immunopathogenesis and investigate the role of RSV strain differences in differential RSV pathophysiology. We are using differentially virulent RSV strains and a RSV reverse genetics system to dissect molecular mechanisms leading to airway mucus expression, bronchiolitis, and pulmonary obstruction in the mouse model. These studies may lead to much-needed effective vaccines and/or therapies for RSV disease.
We are currently pursuing two areas in vaccine research. The first is studying the role of RSV strain variation in immune evasion, using RSV clinical isolates and human sera from a well-defined cohort of RSV-infected children (in collaboration with Dr. Tina Hartert at Vanderbilt University and Drs. Larry Anderson, Dean Erdman, and Teresa Peret at the CDC). The second area of current vaccine research is evaluating RSV vaccine/adjuvant candidates in a preclinical RSV challenge model.
A comprehensive understanding of how RSV strain differences affect pathogenesis and immunity will advance vaccine development and require bridging gaps between basic research, epidemiology, and clinical studies.