Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection.

The innate immune system is a critical component of host defence against microbial pathogens, but effective responses require an ability to distinguish between infectious and non-infectious insult to prevent inappropriate inflammation. Using the important obligate intracellular human pathogen Chlamydia trachomatis; an organism that causes significant immunopathology, we sought to determine critical host and pathogen factors that contribute to the induction of inflammasome activation. We assayed inflammasome activation by immunoblotting and ELISA to detect IL-1β processing and LDH release to determine pyroptosis.

IRE1α mediates PKR activation in response to Chlamydia trachomatis infection.

Protein kinase RNA activated (PKR) is a crucial mediator of anti-viral responses but is reported to be activated by multiple non-viral stimuli. However, mechanisms underlying PKR activation, particularly in response to bacterial infection, remain poorly understood. We have investigated mechanisms of PKR activation in human primary monocyte-derived dendritic cells in response to infection by Chlamydia trachomatis.

Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression.

The endoplasmic reticulum (ER) stress response detects malfunctions in cellular physiology, and microbial pattern recognition receptors recognize external threats posed by infectious agents. This study has investigated whether proinflammatory cytokine expression by monocyte-derived dendritic cells is affected by the induction of ER stress. Activation of ER stress, in combination with Toll-like receptor (TLR) agonists, markedly enhanced expression of mRNA of the unique p19 subunit of IL-23, and also significantly augmented secretion of IL-23 protein.

Spondylarthritis-associated and non-spondylarthritis-associated B27 subtypes differ in their dependence upon tapasin for surface expression and their incorporation into the peptide loading complex.

Objective: B27 subtypes associated with susceptibility to ankylosing spondylitis (AS), and those reported not to be associated with AS, are found to differ in the amino acids that are known in other HLA class I molecules to alter the requirements for tapasin and incorporation into the peptide loading complex. The purpose of this study was to examine the behavior of B*2704 and B*2705 in comparison with B*2706 and B*2709 during early events in HLA class I antigen expression, and determine if their behavior correlates with disease association.

Methods: Cell lines with nonfunctional tapasin were transiently transfected with different B27 subtypes and their site-directed mutants, and surface expression analyzed by flow cytometry.