| Popis: |
Autophagy is a conserved cellular degradation pathway, which involves the delivery of cytoplasmic substrates to lysosomes for degradation. Among 41 identified ATG proteins, ATG5 protein seems to have indispensable role in formation of autophagosome. Autophagy also plays an indisputable role in the regulation of immune response, contributing to the host defense against pathogen. Francisella tularensis, an intracellular pathogen, survive autophagy process, and require autophagy for its intracellular growth. ATG5- dependent autophagy is critical in the regulation of host's innate and adaptive immune response, impacting subsequent inflammatory response as well. IL-1β is an important pro-inflammatory cytokine and its secretion is regulated through the inflammasome induced caspase-1 activation upon infection. The link between autophagy and IL-1β secretion has been interpreted differently. The aim of the study was to investigate an interplay between ATG5-induced autophagy and IL-1β, and their role in pathogenesis of tularemia. We used a model of transgenic mice, lacking ATG5 in cells of the myeloid lineage, bacterium F. tularensis LVS (live vaccine strain) and IL-1β neutralizing antibody. ATG5-deficient and control mice were infected intradermally and IL-1β neutralizing antibody or isotype control antibody were inoculated intraperitoneally. Cytokine and chemokine levels in sera were determined by Luminex assay. Levels of selected pro-inflammatory and anti-inflammatory cytokines in spleen, liver and lungs were analyzed by RT-PCR, and the inflammatory cell infiltration in the lungs and liver were analyzed by immunohistochemistry. Our findings reveal that IL-1β neutralization, together with autophagy deficiency in myeloid cells, increased susceptibility to tularemia. In contrast, treatment of control group of mice with IL-1β antibody, have a beneficial effect on course of tularemia, suppressing bacterial replication and inflammatory response. |
