Dr. Porotto?s research has made significant contributions to the understanding of complex molecular and cellular events involved in the pathogenesis of paramyxoviruses, a family of viruses that includes several important human pathogens. He has focused on two of these pathogens, parainfluenza virus and Hendra virus.
Parainfluenza virus projects: Human parainfluenza viruses are an important cause of croup and bronchiolitis, severe illnesses in young infants, and children worldwide. Respiratory infections including parainfluenza infections are responsible for 20% of the deaths in children under the age of 5 years, worldwide. The goal of one project is to apply our understanding of the fundamental processes of parainfluenza virus entry to the design of novel antiviral drugs. Dr. Porotto and his coworkers have shown that the hemagglutinin-neuraminidase (HN) receptor binding protein, upon binding receptor, triggers the fusion (F) protein to its active state. He is now combining experimental strategies with computational modeling to address fundamental questions about how HN triggers F to fuse the viral envelope with the target cell membrane during entry, and thereby identifying novel therapeutic candidates to inhibit entry. The molecules that Dr. Porotto proposes to design for preventing virus entry are likely to be safe antivirals in infants.

Hendra virus projects: Hendra virus is an emerging paramyxovirus that causes potentially fatal disease in humans. Dr. Porotto is applying an analysis of Hendra virus entry mechanisms to the development of new strategies for inhibiting infection. The first step in infection is the binding of the viral envelope protein G to ephrin B2 or B3 on the cell?s surface. G then activates the fusion protein (F) to its fusion-ready conformation. Insertion of F into the target cell membrane leads to fusion of the viral envelope with the plasma membrane and entry of the virus into the cell. Efficiency of F-triggering by G influences the extent of fusion, and provides a range of strategies for preventing viral entry.

Viral immunopathogenesis and vaccine development: Fundamental information about how the immune response contributes to the development of disease for respiratory viruses is lacking. It is virtually certain that the immune response of the human host plays a large role in determining the course of lung disease. This project addresses the question of the role of paramyxovirus glycoproteins in inducing a harmful inflammatory response in the lung, and considers the nature of the immune response in designing a protective and safe vaccine strategy.