The role of endoplasmic reticulum-related BiP/GRP78 in interferon gamma-induced persistentChlamydia pneumoniaeinfection

Abstract

SummaryDirect interaction of Chlamydiae with the endoplasmic reticulum (ER) is essential in intracellular productive infection. However, little is known about the interplay between Chlamydiae and the ER under cellular stress conditions that are observed in interferon gamma (IFN-γ) induced chlamydial persistent infection. ER stress responses are centrally regulated by the unfolded protein response (UPR) under the control of the ER chaperone BiP/GRP78 to maintain cellular homeostasis. In this study, we could show that the ER directly contacted with productive and IFN-γ-induced persistent inclusions of Chlamydia pneumoniae (Cpn). BiP/GRP78 induction was observed in the early phase but not in the late phase of IFN-γ-induced persistent infection. Enhanced BiP/GRP78 expression in the early phase of IFN-γ-induced persistent Cpn infection was accompanied by phosphorylation of the eukaryotic initiation factor-2α (eIF2α) and downregulation of the vesicle-associated membrane protein-associated protein B. Loss of BiP/GRP78 function resulted in enhanced phosphorylation of eIF2α and increased host cell apoptosis. In contrast, enhanced BiP/GRP78 expression in IFN-γ-induced persistent Cpn infection attenuated phosphorylation of eIF2α upon an exogenous ER stress inducer. In conclusion, ER-related BiP/ GRP78 plays a key role to restore cells from stress conditions that are observed in the early phase of IFN-γ-induced persistent infection.

Chlamydia cell biology and pathogenesis

“…This close contact may facilitate lipid transport 73,74 and the construction of signalling platforms 89 . Membrane contact sites participate in stimulator of interferon genes (STING)-dependent pathogen sensing 90 and could also modulate the endoplasmic reticulum stress response 91,92 . In addition, the inclusion is also juxtaposed to the rough endoplasmic reticulum, forming a `pathogen synapse' (REF.…”

Insights Into the Role of Endoplasmic Reticulum Stress in Infectious Diseases

“…The obligate intracellular pathogen Chlamydia induces the UPR by upregulating BiP (44,45). Chlamydia infection also induces TLR4/IRE1-mediated activation of PKR, which enhances IFN-β production (46).…”

At the crossway of ER‐stress and proinflammatory responses

“…BIP impacts inflammation, notably through an alteration of its subcellular localization and stability . Its distribution is also altered in several neurodegenerative diseases, in cancer and during infections , and its abnormal release in the blood stream induces regulatory myeloid cells, which ablate inflammatory cytokine expression in rheumatoid synovial membrane tissues . BIP is also targeted during bacterial infection, for example, the cholera‐like AB 5 ‐subunit subtilase toxin can enter the ER lumen and induce degradation of BIP, activating the UPR and creating permissive conditions for bacterial replication .…”