Innate immune parameters leading to virus-induced secondary bacterial pneumonia and sepsis.

Influenza virus causes significant illness and death annually, which drives the development of vaccines for those most at risk. However, it is not widely appreciated that influenza does not always act alone. In combination with bacteria, this viral disease is much worse and the prognosis poor. This is not simply a problem with seasonal influenza virus strains. Recently, researchers have re-analysed specimens taken from those that died during the most severe pandemics and revealed a plethora of bacterial species. In a large proportion multiple bacterial species were present. Why do they cause a problem in some influenza infected individuals and not others? We believe that an individuals past infection history and consequent status of immune cell activity are responsible. We have evidence that influenza alters the activity of key anti-bacterial immune cells in the lower airways rendering them un-responsive to bacteria where they expand and cause pneumonia. We will now dissect this effect to gain a better understanding of the full complexities of this combined infectious disease. Such analysis may identify critical pathways that allow this virus-induced bacterial problem to occur in the first place, which will assist in the identification of those most at risk and potential avenues for targeted treatment. We will also analyse the impact of antibiotics that have different modes of action since it is clear that some strategies result in a worse outcome. The research will provide a possibility for better informed patient management in the future.

Secondary bacterial pneumonia is a common occurrence after lung influenza virus infection and leads to a significantly worse prognosis. It is now apparent that 4 to 14 days after resolution of influenza-induced symptoms a recurrence of fever, dyspnea, productive cough, and pulmonary consolidation arises in some due to a bacterial super infection, most commonly caused by Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae. Bacterial complications are not restricted to seasonal influenza strains. A recent re-analysis of post mortem specimens from past influenza pandemics show a previously unappreciated high frequency of bacterial species in the lower airways that are usually restricted to the nasopharynx. We have recently published two key influences of influenza on the lung that are likely to contribute to bacterial susceptibility: 1) a long term de-sensitisation of alveolar macrophages to subsequent bacterial products and 2) an increase of macrophage innate immune regulatory pathways that reduce their immediate response to bacteria. Using robust viral/bacterial co-infection models in mice we have generated preliminary data showing that a severe outcome correlates with entry of lung bacteria into the blood. Furthermore, we show that systemic spread of bacteria is critically determined by the state of activation of innate immune cells in the airways. Lowering the threshold above which myeloid cells respond to bacteria (by removing a negative regulator) limits bacterial replication in the lung and prevents sepsis and death. We now take this important concept further to ask: 1) how does the balance of immune potentiators and negative regulators influence the bacterial super-infection following influenza? We will develop the system further to examine the critical role of the epithelium in controlling myeloid cell activity and 2) determine which type of antibiotic is beneficial to prevent bacterial complications following influenza, when they should be administered and whether a peripheral inflammatory mediator profile exists that might assist antibiotic choice. These key questions will provide a detailed and mechanistic insight into the clinically important problem of bacterial super-infections that are likely to have direct clinical implications.