The host response to influenza virus/bacterial pulmonary coinfection

Pneumonia is an important global health problem, and is the leading cause of death of children under five years of age. Influenza virus is one of the most prevalent causes of viral pneumonia, and often an infection with influenza virus leads to subsequent complications with bacteria that cause pneumonia. Given the prevalence of viral/bacterial lung coinfections understanding the mechanisms involved in the response to them is an important area of study. The ability to survive an infection depends on both resistance to the pathogen(s) (i.e. clearance of the pathogen(s)), and tolerance of the damage caused either by the pathogen(s) directly or by the immune response fighting them. Simultaneous infection with two different pathogens can affect resistance, tolerance, or both. Pneumonia caused by the bacterium Legionella pneumophila is emerging as a common complication of influenza virus infection. We have developed a mouse model of influenza virus/L. pneumophila lung coinfection to study this problem in a tractable system. Interestingly, influenza virus/L. pneumophila coinfection causes increased lethality without an increase in viral or bacterial load. This is distinct from other studies of coinfection, where the pathogen burden is increased causing pathology, thus obscuring the effects of the host response. There is no obvious change in resistance mechanisms, but there is a decreased ability to tolerate the coinfection compared to single viral or bacterial infections. We will examine if the reason for the decreased tolerance is due to a more destructive immune response or by a decreased ability to repair damage caused by the pathogens and/or the immune response. We will study changes in the immune response and changes in tissue repair mechanisms that occur during influenza virus/L. pneumophila coinfection, and the effect these changes have on the outcome of the coinfection. This model system will enable us to study an important clinical problem; in addition, since resistance against the pathogens is unchanged, we will be able to thoroughly examine the effect of coinfection on tolerance mechanisms.

Seasonal influenza virus infection affects 5-15% oft the worlds population. Influenza-related premature deaths are estimated at 40.000 per year in the European Union. Many-if not most-deaths associated with Influenza virus are not caused by the virus alone, but rather by concomiatant bacterial pneumonia. This notion is supported by post-mortem analyses of victims that succumbed to the spanish flu pandemic of 1918/1919. Therefore, medication against severe influenza must take potential bacterial superinfection into account.The aim of project P 25235-B13 was to investigate the interplay of influenza virus with Legionella pneumophila, a causative agent of bacterial pneumonia. Because the lung is not considered a sterile organ and most likely inhabited by commensal microbes and/or opportunistic pathogens a second, long-term aim of our studies is to define the lung microbiome and to analyse its changes upon flu infection.Within the period supported by the FWF we could establish the balance between antibacterial immune mechanisms and tolerance to sequels of infection as a fundamental determinant of infection outcome. Infection with influenza virus did not enhance or otherwise alter the ability of Legionella to multiply in infected lungs. Vice versa, influenza virus replication was not enhanced by the concomitant presence of Legionella. In spite of this, coinfection strongly increased the mortality of infected animals. We realized that compared to infection with influenza virus alone, coinfection strongly impaired the ability of the host to cope with the consequences of the accompanying inflammatory process. In particular, cell types and genes associated with tissue repair were less frequent and/or suppressed in their activity. Consistent with this, application of a substance enhancing tissue repair partially reversed the adverse impact of coinfection.Our studies thus establish tolerance to infection as an important parameter determining lethal outcome. They further show that reduction of tolerance may be the main consequence of an interplay of microbes upon coinfection.