Pathogenesis of Pneumoviruses
Human respiratory syncytial virus (RSV) is the leading viral agent of serious lower respiratory tract disease in infants and children up to the age of two. Additionally, RSV is being recognized as important pathogen in the elderly and in immunocompromised patients. However, an effective antiviral therapy or a licensed vaccine is lacking despite major efforts over decades, likely due to a fragmentary understanding of pathogenicity mechanisms and lack of a permissive animal model. Infection of mice with the closely related pneumonia virus of mice (PVM) causes symptoms that are similar to those induced by RSV-infection of humans. Subsequently, we are using the PVM-infection as a surrogate model to study pneumoviral pathogenicity. Recently, we developed a reverse genetic system for PVM permitting directed mutagenesis of the viral genome and recovery of infectious virus from cloned cDNA, and, thus, permitting identification and analysis of pathogenicity factors of virus and host. The following projects are currently investigated:
1. Pulmonary innate and adaptive immunity in a natural infection model for pneumoviruses.
This is a collaborative project between the research groups of Prof. Dr. S. Ehl, Center for Chronic Immunodeficiency, University Hospital of Freiburg, (T cell response following PVM infection) and Dr. Krempl (aspects of innate immunity). The synthesis of interferon α/β and of the recently identified interferon λ represents the first and immediate antiviral response of a cell, respective organism, to infection by viruses. RSV, and also PVM, encodes two non-structural proteins, NS1 and NS2, that are potent inhibitors of the interferon response in vitro. However, only few in-vivo data are available up to date. Thus, by using recombinant PVM with deletion of the NS genes, the PVM model provides the opportunity to study the role of interferon α/β and λ in replication and pneumoviral pathogenicity in the course of a natural infection. In addition, the model permits investigation of the influence of the immediately occurring interferon response on the development of the virus-specific T cell response.
2. Pathogenesis of pneumoviral infections after hematopoietic stem cell transplantation.
Infections with RSV represent major complications after hematopoietic cell transplantation (HCT) and are associated with high morbidity and mortality. The mechanisms leading to these severe problems of HCT recipients differ from the pathomechanisms in immunocompetent patients, but are not well understood.
In this project we will establish a species-conform HCT-infection model utilizing PVM to investigate the pathomechanisms of pneumoviral infections after HCT. We expect to gain significant insight into the pathogen-host-interactions of respiratory infections in immunocompromised hosts that will provide the basis for development of effective therapies of these severe complications.