Viruses can predispose the host to bacterial superinfection, and secondary pneumonia is considered to play a major role in the morbidity of seasonal as well as pandemic influenza. Despite the significant clinical and socioeconomic impact, the molecular mechanisms of how influenza virus causes superinfection have been poorly understood. Scientists from Andreas Bergthaler´s Group at CeMM now succeeded in finding a new molecular mechanism, which may explain why influenza virus infections increase the susceptibility to bacterial pneumonia. Their discovery of a novel crosstalk between the antiviral molecule interferon and the enzyme Setdb2, which weakens the antibacterial response has been published advanced online on November 24th, 2014 in the scientific journal Nature Immunology.
During seasonal flu epidemics, respiratory infections with influenza virus lead to a sudden onset of high fever, cough, headache, runny nose, sore throat and other signs of fatigue and general discomfort. High-risk groups such as very young, elderly or chronically ill people may develop severe disease, which results in approximately 500.000 deaths annually (WHO). These severe influenza cases are often associated with secondary bacterial infections, so-called superinfections. Past studies suggested that the virus is not the primary cause of disease. Instead, the trigger for disease seems to be the suppression of the immune system by the virus.
Using a superinfection model of influenza virus and streptococci, Bergthaler´s group could now show that interferon, which plays a central role in the antiviral response, induces the enzyme Setdb2. Subsequently they found that Setdb2 blocks the expression of antibacterial genes such as the chemoattractant Cxcl1, which is crucial for the recruitment of immune cells to the lungs and the control of bacterial infections. This mechanism may avoid excessive inflammation during viral infection. At the same time, however, it renders the organism more vulnerable to bacterial superinfection. Future research aims to elucidate the complex molecular interplay between the virus, Setdb2, the bacteria and the immune system. This may open new potential therapeutic avenues for patients at risk of superinfections.
Setdb2 mediates virus-induced susceptibility to bacterial superinfection.
Christopher Schliehe, Elizabeth K. Flynn, Bojan Vilagos, Udochuku Richson, Savitha Swaminanthan, Berislav Bosnjak, Lisa Bauer, Richard K. Kandasamy, Isabel M. Griesshammer, Lindsay Kosack, Frank Schmitz, Vladimir Litvak, James Sissons, Alexander Lercher, Anannya Bhattacharya, Kseniya Khamina, Anna L. Trivett, Lino Tessarollo, Ildiko Mesteri, Anastasiya Hladik, Doron Merkler, Stefan Kubicek, Sylvia Knapp, Michelle M. Epstein, David E. Symer, Alan Aderem and Andreas Bergthaler. Nature Immunology AOP, Doi: 10.1038/ni.3046
The study has been funded by CeMM, the Austrian Academy of Sciences (ÖAW), the Austrian Science Fund (FWF), the German Academic Exchange Service (DAAD), the Swiss Foundation for Grants in Biology and Medicine (SSMBS), the Swiss National Science Foundation (SNF) and the US National Institutes of Health (NIH).