Immune Response to Influenza Infection

We study immune responses to Influenza infection and how the immune system contributes to damage and protection of the patient. Influenza, commonly called the Flu, and other infections of throat and lung are often harmless but sometimes lead to severe damage and even death. Different Flu viruses cause disease of different severity, indicating that viral factors influence disease outcome. Also, when different persons are infected by the same Flu virus, the clinical outcome can vary widely, showing that factors in the individuals body make a difference in the disease. The immune system is necessary to eliminate the virus but in the process contributes to lung damage. The rules in this battle between virus and immune system are not clear, and therefore, the outcome of infection cannot be predicted. Which factors can tip the balance between damage or death on one side and successful clearance of the virus on the other is not completely known. Our studies serve to understand better which characteristics of the virus and of the infected organism can change disease outcome. We attempt to identify factors that contribute to eliciting a strong immune response and to causing lung damage. Better knowledge of these factors will help design better medical intervention during Flu infection.

We study early immune events in Influenza infection, specifically the interface between infected lung epithelium and innate immunity. The aim of our studies is to identify determinants of immunogenicity and pathogenicity in influenza virus infection and the immune response to it. Respiratory tract infections by bacteria and viruses are still one of the leading causes of death worldwide. Among these infections, seasonal influenza epidemics represent a constant burden to public health, and influenza pandemics caused by new strains pose a serious global threat. Despite this, it is largely unclear which mechanisms can tip the balance between self-limiting infection on one hand and morbidity and mortality due to lung pathology on the other hand. Influenza virus itself is cytopathic, and the immune response is necessary to eliminate the virus, but also involved in immune-mediated damage to lung tissue. It is still unclear how infected epithelial cells activate the immune system, how early events in the infection influence the induction of the immune response, and which viral and host factors are determinants for a protective or fatal outcome of infection. Work in this programme focuses on these early events and on the relationship between infected epithelial cells and immune cells. We have set up airway epithelial cell cultures from primary cells and now study how they activate innate immunity. In vitro work will be done both with wild-type and mutant murine cells and with human cells. These studies will be complemented by in vivo work using bone-marrow chimeras to assess the contribution of epithelial cells to the onset of anti-influenza immune responses. We will attempt to visualize viral infection by reporter gene strategies, to follow infection in vivo and perform functional tests on infected cells. We will assess the role of NK cells and neutrophils in the immune response to and immunopathology caused by influenza virus infection. Since co-infection by gram-positive bacteria is an important clinical complication of influenza infection, we will determine factors by which the viral infection sets the stage for subsequent bacterial attack. All these studies are instrumental to understand respiratory viral infections better, to predict their outcome and to identify modes of intervention that enhance protection and prevent damage.