In an article entitled, ‘A Systems Analysis Identifies a Feed forward Inflammatory Circuit Leading to Lethal Influenza Infection,’ published in July 3, 2013 issue of Cell (vol. 154, issue 1; 197-212), the lead author Marlène Brandes at the Lab. Systems Biology at the National Inst. of Allergy and Infectious Diseases, NIH, Bethesda, MD with three associates affiliated to different organizations has shown that excessive early immune responses contribute to deaths caused by certain influenza viruses. Scientists found that reducing the number of inflammatory immune cells in the lungs of mice increased the animal’s survival after infection with a virulent flu strain. In this study they first infected mice with an influenza strain that mimics the effects of the H1N1 virus that caused the 1918 flu pandemic. Then they assessed the animal’s immune function at the gene, cell, and tissue level and compared that to those of healthy mice and mice infected with a non-lethal H1N1 strain. Their initial studies suggested that infection-fighting immune cells called neutrophils may influence whether flu infections are deadly or not. Further analysis showed that neutrophils began to accumulate in the lungs of mice infected with the lethal flu strain within two days of infection, several days before the animals became severely ill. The researchers also observed that the neutrophils release pre-formed proteins such as the Interleukin 1 (IL-1), and produce other chemicals that attract more neutrophils to the infection site in a potentially explosive amplification process. They predicted that blunting this amplification process might protect the mice from lethal immune damage. To test this prediction, the investigators reduced neutrophil numbers in infected mice by giving the animals a neutrophil-depleting antibody. Mice given low doses of the antibody survived longer than those that did not receive the antibody. However, animals treated with high doses of the antibody died prematurely, suggesting that too much neutrophil depletion may have interfered with beneficial immune responses. The study in mice provides direct evidence that damaging inflammation caused by the immune system’s initial response to H1N1 infection can be a major contributor to death. The new findings raise the possibility that other infectious diseases that cause life-threatening lung injury, such as H7N9 influenza and SARS, might elicit similar immune reactions. Another novel finding from this study is that neutrophils continually produce IL-1. This raises the question of whether drugs that blunt the function of IL-1 might help limit neutrophil activation and subsequent lung damage in people with the flu, while preserving the essential immune functions of IL-1.
[Summarized by Samsad Razzaque a Research Associate in the Plant Biotech Lab, DU].