Aspects of Innate and Adaptive Immune responses during Respiratory Syncytial Virus Infection

Abstract

Respiratory Syncytial Virus (RSV) infections are a major cause of lower respiratory tract disease and represent a major disease burden in infants, immune compromised patients and the elderly. Despite the identification and isolation of the virus in 1956, extensive efforts since then to develop a safe vaccine or effective antiviral therapy are without clear success. A vaccine trial in the 1960s caused enhanced disease when vaccines were exposed to the natural virus. The only approved intervention is the use of a prophylactic monoclonal antibody which is applied in high risk infants. Adaptive memory responses elicited during natural infections with RSV do not provide complete protection. The exact mechanism behind severe primary disease in humans is still poorly understood, and the mechanism behind vaccine enhanced respiratory disease while studied extensively in mouse models have not lead to clear insights for better vaccine approaches. Thorough knowledge of the complex interactions between the virus and the host immune system might eventually bring to light alternative strategies to protect against severe RSV infections, but this remains a great challenge. In the past 50 years, since its initial discovery, many studies have been performed that have shed light on epidemiology, disease, immunity and vaccine development in relation to RSV. Major questions that remain are; (I) why do certain otherwise healthy children develop severe RSV lower respiratory tract infection, while the majority of the birth cohort presents with a mild disease? (II) Why is immunity to RSV incomplete and are healthy persons frequently re-infected? (III) How to protect those at risk for severe RSV disease, is vaccination for RSV desirable at young age or are there alternative methods more suitable and effective? In this thesis we try to shed light on certain aspects of these questions by studying the involvement of different cell types and their pathogen recognition receptors in the induction of RSV specific responses in mouse models and the kinetics of primary immune response in children with severe RSV infections. In conclusion, although the exact mechanism of severe RSV disease in humans is still unclear, the sequence of events during severe primary RSV infection in infants indicates that T cells are probably not directly contributing to disease severity. The lack of a clear correlation between viral load and disease indicates that modulation of innate immunity during infection should be considered an alternative strategy to reduce illness. Furthermore, humans are capable of generating highly neutralizing antibodies that can limit viral load, but not completely protect against frequent re-infections indicating complex interactions between RSV and protective innate and T cell responses. Caution should be taken in directly translating data obtained from murine studies to the human system as different parameters of the infection are responsible for disease.