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Innate-Like T-Cells In Sepsis (ILTIS): Implications for Early Diagnosis and Rescue of Immune Suppression.

Periodic Reporting for period 1 - ILTIS (Innate-Like T-Cells In Sepsis (ILTIS): Implications for Early Diagnosis and Rescue of Immune Suppression.)

Reporting period: 2017-09-01 to 2018-08-31

"Problematic: Research on infectious diseases has high priority for the scientific and medical communities worldwide, to tackle the alarming spread of multidrug resistant bacteria, to fight and prevent virus outbreaks, and to improve patient management in severe infections including sepsis. Sepsis is recognised as one of the biggest challenges in modern healthcare. It kills as many as 30% of affected patients and leaves a lasting legacy even in those that survive. Although effective antimicrobials can improve the outcome of sepsis, diagnosis of the underlying infection is difficult and possible only in less than 60% of cases. A better understanding of the cellular and molecular signatures in acute disease may pave the way to earlier and more accurate diagnosis, targeted and personalised treatments and thus better outcomes. Research in the host laboratory at Cardiff University (Division of Infection and Immunity, School of Medicine) has shown that microbes interact at various levels with the immune system and leave disease-specific ""immune fingerprints"" that discriminate between different groups of organisms and inform the design of novel tests for infection diagnosis. Among the major breakthroughs in the understanding of host innate immune responses is the characterization of innate-like or unconventional T cells such as γδ T cells and mucosal-associated invariant T (MAIT) cells in acute disease. The organisms sensed by one or both of these unconventional T cell subsets include the causative agents of global health threats like tuberculosis and most hospital-acquired infections.
Objectives: The aim of the proposed project was to study the phenotype and function of innate immune cells during acute sepsis, with a particular focus on γδ T-cells and mucosal-associated invariant T (MAIT) cells. This translational research involved bed to bench-side approaches and addressed the potential of unconventional T cells to be exploited for novel diagnostics to predict the causative pathogen long before traditional culture results become available, and for novel therapies aimed at overcoming the detrimental immunosuppression frequently observed in sepsis and that is associated with poor clinical outcomes and elevated susceptibility to fatal second-hit infections.
During the project period (one year: 01/09/2017 – 31/08/2018) the research performed at the host institution achieved processing of blood samples from sepsis patients as well as controls. Sepsis patients were recruited during severe sepsis/septic shock after admittance in intensive care unit. Controls were healthy volunteers matched for age and gender. The samples were analysed for cell-surface markers indicating cell activation/differentiation status (immune phenotype) and also for cell functions during cell culture experiments.
Phenotypic analyses of circulating immune cells were performed in conventional (CD4+ and CD8+ T-cells) and unconventional T cells (γδ T-cells and MAIT cells). Results indicate a clear distinction between sepsis and controls for the cell activation status. Further analysis is ongoing to see if the combination of these phenotypic markers with soluble markers (e.g. cytokines) may be useful to determine the “immune fingerprints” related to specific microorganisms.
The research also included in vitro experiments with unconventional T cells from patients with ongoing sepsis. We studied the interaction between two categories of immune cells: monocytes and γδ T-cells. Previous work showed that γδ T-cells had the ability to stimulate monocytes and induce an inflammatory phenotype. We confirmed that monocytes had an attenuated response during sepsis. This could be overcome by stimulating cytokines but not by stimulation of γδ T-cells. These experiments allowed discoveries that improved the understanding of sepsis-induced immune suppression mechanisms.
Exploitation of the results comprises writing of a scientific publication, collaboration with an industrial partner to assess and exploit the potential of new molecules to overcome sepsis-induced immunosuppression, and initiation of a new research project that will benefit from these results to test new markers for immune fingerprints characterization during sepsis.
Dissemination will be made through scientific journals, and public medias.
The limited data acquired during the study period laid the foundation for the discovery of new tools for sepsis diagnosis management. While we do not see a direct socio-economic or societal impact of this research, research in the host institute is ongoing and we expect to analyse data on a larger scale and including information from a large set of soluble markers. Regarding the in vitro experiments we retrieved promising results about monocytes and γδ T-cells interactions during the septic process.
image summary ILTIS