As resistance to antibiotics peaks, alternative strategies to fight infection, like boosting our body’s innate immunity, are being explored.
Bengaluru: Inflammation, the redness and swelling that accompanies most kinds of injury or infection, is one of the body’s first lines of defence. It indicates that blood, which is populated by important immune cells, is being directed to that area – generally a good sign that our innate immune system is alive and kicking.
However, sometimes things can go awry. “It is important for the immune response to regulate inflammatory responses because too much can hurt the body,” said Dipankar Nandi, immunologist at Indian Institute of Science, Bengaluru. The collateral damage could range from fever and pain to tissue destruction and organ failure. In a study published on April 27 in the journal Science Translational Medicine, scientists from Lund University, Sweden, describe a potential way to filter out the bad effects and only keep the ‘good’ kind of inflammation.
The team, led by Manoj Puthia, focused on specific genes that were known to regulate innate immune responses to bacterial infection, in this case a urinary tract infection called polynephritis which is caused by Escherichia coli. “We sought ways of selectively attenuating the destructive aspects of the innate immune response that cause symptoms and tissue damage, without jeopardising the antibacterial defence,” said Puthia.
A surprising interplay
A molecule called IRF3 had recently been identified as crucial for the body to activate an innate immune response against polynephritis. Mice without the Irf3 gene developed severe symptoms, uncontrolled inflammation and kidney damage. Humans with variations in their IRF3-related genes were also found to be highly susceptible to recurrent polynephritis, further bolstering the hypothesis.
In the current study, Puthia and team discover that another molecule IRF7, which along with IRF3 mediates immune response against viral infections, plays an opposing role to IRF3 when it comes to polynephritis. Mice without the Irf7 gene rapidly cleared pathogenic E. coli without any evident tissue damage. “Our results suggested that suppression of Irf7 might be beneficial, identifying Irf7 as an immunotherapeutic target,” said Puthia.
To further explore Irf7’s potential as a target, they introduced siRNA to IRF3-blocked mice. siRNA, or small interfering RNA, are small fragments of RNA that are designed to silence specific genes, in this case Irf7. As suspected, the mice, which previously had suffered grave kidney damage, now stopped producing IRF7 and were protected against infection and renal tissue damage.
An alternative worth exploring
The idea of equipping the body to fight off an infection by boosting innate immunity is often discussed as a possible alternative to antibiotic therapy, especially in the light of the antibiotic resistance crisis. However, this boosting has to be done in such a way that exaggerated inflammation does not occur. This is where the authors believe that their finding becomes relevant.
Satyajit Rath, a pathologist at National Institute of Immunology, Delhi, who was not involved in the study said that while such strategies are worth exploring, he sees them not as ‘instead of’ antibiotics but ‘in addition to’. “They are useful for situations of antibiotic resistance,” he said, adding that we should be wary since there has been some recent evidence that they may well modulate antibiotic resistance, too. “And they can potentially have major problematic side effects, especially if needed for intermediate/long-term usage, since the immune/inflammation modulation is unlikely to be target-specific.”
Puthia acknowledged this concern. “As Irf7-blocked mice are susceptible to viral infections, long-term, systemic IRF7 inhibition could have side effects and should be avoided,” he said. However, he added that in a treatment setting analogous to antibiotic therapy, IRF7 inhibition would be temporary, making this an unlikely concern.
The team have many plans for the future. “We are in the process of planning a nation-wide clinical study in polynephritis patients to validate the genetic predisposition and identify suitable patient groups.” They also plan to investigate if siRNA is the best way to attenuate IRF7 or if other technical solutions will be more suitable in clinical studies. “If successful, these findings open new doors to treat infections, in particular where antibiotics are failing,” said Puthia.