Salmonella Exhibit Altered Cellular Localization in the Presence of HLA-B27 and Codistribute with Endo-Reticular Membrane

Salmonella enteritica (S. enteritica) induce and require unfolded protein response (UPR) pathways for intracellular replication. Salmonella infections can lead to reactive arthritis (ReA), which can exhibit associations with Human Leucocyte Antigen (HLA)-B ∗ 27 : 05. S. enteritica normally reside in a juxtanuclear position to the Golgi apparatus, representing the formation and residence within the Salmonella-containing vacuole (SCV). Changes in cellular localization of infecting Salmonella can alter their ability to replicate. We therefore used isogenic epithelial cell lines expressing physiological levels of HLA-B ∗ 27 : 05 heavy chain (HC) and a control HLA-B allele, HLA-B ∗ 35 : 01.HC to determine any changes in Salmonella localization within epithelial cells. Expression of HLA-B ∗ 27 : 05 but not HLA-B ∗ 35 : 01 was associated with a quantifiable change in S. enteritica cellular distribution away from the Golgi apparatus. Furthermore, the Salmonella requirements for UPR induction and the consequences of the concomitant endoplasmic reticulum (ER) membrane expansion were determined. Using confocal imaging, S. enteritica bacteria exhibited a significant and quantifiable codistribution with endo-reticular membrane as determined by ER tracker staining. Isogenic S. enterica Typhimurium mutant strains, which can infect but exhibit impaired intracellular growth, demonstrated that the activation of the UPR was dependent on an integral intracellular niche. Therefore, these data identify cellular changes accompanying Salmonella induction of the UPR and in the presence of HLA-B27

Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication

A.N.A was funded by ARUK Fellowships Non-Clinical Career Development Fellowship Ref No: 18440. I.L. was funded by an ARUK PhD studentship Ref No: 17868. A.N.A and S.J.P were also in part funded by ARUK (grant 21261)Objective Salmonella enterica infections can lead to Reactive Arthritis (ReA), which can exhibit an association with human leucocyte antigen (HLA)-B*27:05, a molecule prone to misfolding and initiation of the unfolded protein response (UPR). This study examined how HLA-B*27:05 expression and the UPR affect the Salmonella life-cycle within epithelial cells. Methods Isogenic epithelial cell lines expressing two copies of either HLA-B*27:05 and a control HLA-B*35:01 heavy chain (HC) were generated to determine the effect on the Salmonella infection life-cycle. A cell line expressing HLA-B*27:05.HC physically linked to the light chain beta-2-microglobulin and a specific peptide (referred to as a single chain trimer, SCT) was also generated to determine the effects of HLA-B27 folding status on S. enterica life-cycle. XBP-1 venus and AMP dependent Transcription Factor (ATF6)-FLAG reporters were used to monitor UPR activation in infected cells. Triacin C was used to inhibit de novo lipid synthesis during UPR, and confocal imaging of ER tracker stained membrane allowed quantification of glibenclamide-associated membrane. Results S. enterica demonstrated enhanced replication with an altered cellular localisation in the presence of HLA-B*27:05.HC but not in the presence of HLA-B*27:05.SCT or HLA-B*35:01. HLA-B*27:05.HC altered the threshold for UPR induction. Salmonella activated the UPR and required XBP-1 for replication, which was associated with endoreticular membrane expansion and lipid metabolism. Conclusions HLA-B27 misfolding and a UPR cellular environment are associated with enhanced Salmonella replication, while Salmonella itself can activate XBP-1 and ATF6. These data provide a potential mechanism linking the life-cycle of Salmonella with the physicochemical properties of HLA-B27 and cellular events that may contribute to ReA pathogenesis. Our observations suggest that the UPR pathway maybe targeted for future therapeutic intervention.Publisher PDFPeer reviewe

Organizational commitment and knowledge sharing in contemporary companies

Książka przedstawia pojęcie zaangażowania organizacyjnego, czym ono jest oraz jak wykorzystywać i rozumieć wartość zarządzania wiedzą i dzielenia się nią zarówno dla pracowników, jak i organizacji jako całości. Wnikliwa analiza literatury światowej ukazuje zaangażowanie organizacji i dzielenie się wiedzą jako kluczowe determinanty efektywności procesu zarządzania organizacją, w tym zarządzania kapitałem ludzkim. O ile w literaturze przedmiotu dużo miejsca poświęca się eksploracji ww. pojęć, traktowanych jako kategorie podlegające odrębnej analizie, o tyle diagnozę i analizę związku między nimi należy traktować jako proces słabo rozpoznany. Ta książka wypełnia lukę badawczą, dostarczając teoretycznej podstawy i ważnych informacji na temat zaangażowania organizacyjnego i dzielenia się wiedzą, podkreślając związek między obiema kategoriami badań.When evaluating the success of an organization, the value of employees’ organizational commitment and the process of knowledge sharing among staff must be considered. As illustrated in this volume, these two concepts are key conditions for organizational success in the contemporary world. This book explores the concept of organizational commitment, what it is, and how to use and understand the value in knowledge management and sharing for both employees and organizations as a whole. A profound analysis of the global literature exposes organizational commitment and knowledge sharing as key determinants of the effectiveness of the organization management process, including human capital management. While much space in the literature on the subject is devoted to the exploration of the above-mentioned concepts, treated as categories subject to separate analysis, the diagnosis and analysis of the relationship between them should be treated as a poorly recognized process. This book fills a research gap, providing a theoretical foundation and important information on organizational commitment and knowledge sharing, highlighting the relationship between both research categories. It will be of interest to researchers, academics, practitioners, and students in the fields of human resource management, leadership, and organizational studies

The MHC Class I heavy chain structurally conserved cysteines 101 and 164 participate in HLA-B27 dimer formation.

AIMS The human leukocyte antigen (HLA)-B27 is strongly associated with a group of inflammatory arthritic disorders known as the spondyloarthropathies (SpAs). The unusual biochemistry of HLA-B27 has been proposed to participate in disease development, especially the enhanced ability of HLA-B27 to form several heavy chain-dimer populations. HLA-B27 possesses three unpaired cysteine (C) residues at position 67, 308, and 325, in addition to the four conserved cysteine residues at p101, 164, 203, and 259. C67 was proposed to participate in dimer formation of recombinant HLA-B27 protein and in vivo heavy chain-dimers. However, the structurally conserved C164 was demonstrated to participate in endoplasmic reticulum (ER) resident heavy chain-dimer formation. We therefore wanted to determine whether these aggregates involve cysteines other than C164 and the basis for the difference between the observed heavy chain-dimer species. RESULTS We determined that C164 and C101 can form distinct dimer structures and that the heterogenous nature of heavy chain-dimer species is due to differences in both redox status and conformation. Different HLA-B27 dimer populations can be found in physiologically relevant cell types derived from HLA-B27-positive patients with inflammatory arthritis. In addition, HLA-B27 dimer formation can be correlated with cellular stress induction. INNOVATION The use of both mutagenesis and manipulating cellular redox environments demonstrates that HLA-B27 dimerization requires both specific cysteine?cysteine interactions and conformations with differing redox states. CONCLUSION HLA-B27 heavy chain-dimerization is a complex process and these findings provide an insight into HLA-B27 misfolding and a potential contribution to inflammatory disease development