A mechanism that causes the body to sabotage its own defenses against infection by visceral leishmaniasis has been discovered. According to researchers from Institut National de la Recherche Scientifique (INRS), this discovery, published yesterday in Cell Reports, could help in the fight against a number of chronic infections.
Like many chronic infections, visceral leishmaniasis thwarts the immune system's defenses so it can settle comfortably into its host. Professor Simona Stäger's team at INRS discovered the mechanism that Leishmania donovani takes advantage of to sustain the infection, and also showed that damage from chronic inflammation induces the death of white blood cells essential to eliminating the parasite.
At the heart of the immune response, CD4 T cells are essential to controlling an infection. This type of white blood cell participates in the immune response by signaling the presence of a pathogen to be eliminated. To do this, CD4 T cells produce interferon gamma (IFN-γ), which activates the cells that destroy pathogens. In the case of visceral leishmaniasis, CD4 T cells expressing IFN-γ (Th1 cells) appear later than expected during infection and in smaller numbers.
To understand how CD4 T cells are dying, researchers followed a lead identified in one of their recent studies. They had noticed the presence of a transcription factor unusual for these cells. The detected factor, IRF-5, is known for its action in innate immunity cells, but is role was totally unknown in CD4 T cells.
Professor Stäger's new findings show that IRF-5 leads Th1 cells to self-destruct. Tracing the thread of molecular events, the immunologist pinned down the trigger for this unexpected cell death: tissue destruction. Following a series of reactions, which are still not fully understood, the destroyed tissue activates previously unknown signals in Th1 cells, causing them to die.
The white blood cells that orchestrate the attack are thus eliminated—not by the parasite but by a biological process of the host—sustaining the chronic infection and protecting the parasite. In fact, this mechanism may also be at play in other chronic infections that lead to inflammation, Stäger reports.
Image: The study presented by Professor Simona Stager's team points to a mechanism involving the TLR7 receptor (Toll-like Receptor 7), usually activated in innate immune system cells by pathogen recognition. In the case of chronic inflammation, the cellular residues present after tissue destruction activate TLR7 in Th1 cells. Activation of TLR7 induces expression and activation of IRF-5, which in turn increases expression of DR5 (Death Receptor 5) and caspase 8, two signaling elements leading to cell death. Thus, chronic inflammation induces the death of protective CD4 T cells via the TLR7-IRF-5 cellular pathway. Image courtesy of INRS.