| Abstract |
The immune system patrols the body constantly in search of "danger" signals derived from microbes or injuries. This response occurs in an innate (inborn) manner where all cells respond in a pre-programmed way, independently of previous infections or immunisations. In many scenarios this early phase of immunity is sufficient to control the infection. In other cases, a second "smarter" wave, the so-called acquired or adaptive immune response, needs to kick in. Certain white blood cells, so-called T cells, carry highly specific receptors, with each individual cell displaying a unique and distinct specificity to microbial molecules such that no two T cells in the body are identical. During infection, those T cells with the strongest potential to mount an effective response will become selected, increase in numbers and develop long-lasting memory against this pathogen. This process is also the mechanism underlying successful immunisations. A subgroup of T cells behaves in an "unconventional" manner as they appear to detect infections in a pre-programmed fashion and much more rapidly than normal T cells. These unconventional T cells are heavily under-researched and their roles in the immune system very ill-understood, compared to other more "classical" immune cells. This is due to the fact that those unconventional T cells cannot be examined using traditional models and methods; in essence they comprise an entirely unique aspect of immunity that requires researchers to think outside the box. Research by us and others has shown that unconventional T cells in fact constitute highly specialised cells that play a crucial role in detecting invading germs very early on in infection. This detection affects whether and how other immune cells become involved in the antimicrobial response, which ultimately determines how long the infection may last. We will here study patients with acute infections in their belly, from whom we obtain small samples for the analysis of their immune response. We will collect blood and waste fluid from individuals on home dialysis while they are healthy, and from those unfortunate individuals who may develop an infection during the study period. By comparing the differences between the healthy status and infection we can learn how the immune system responds rapidly to microbial insults. These investigations will be combined with laboratory studies that aim at mimicking the situation at the site of infection as closely as possible. For these experiments in cell culture dishes, we will isolate different types of white blood cells, including unconventional T cells, and study their interaction with each other and the outcome of their responses to bacterial pathogens. The present proposal provides a detailed characterisation of unconventional T cells during microbial infections at the site of infection (belly), before treatment with antibiotics commences. Such an investigation has never been attempted before but is urgently needed to demonstrate as to how much laboratory-based studies can actually teach us about real infections. These studies not only improve our insight into the complex cell interactions in early infection but will also help identify new markers for future diagnostic tests. Such tests may be able to use unconventional T cells and related parameters to tell the clinician which type of germs actually causes the infection and how best to treat the infection (and avoid having to give unnecessary treatments that are both costly and may cause harm to the body). Finally, our findings will also highlight new avenues for treatments by interfering with the unconventional T cell-induced responses, by improving recovery from infection and by dampening collateral damage on healthy tissues and organs. In a world where people increasingly suffer from conditions related to advanced age (including loss of kidney function), this research will ultimately improve the quality of life of such patients. |