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Orientia tsutsugamushi Ank effectors target lamin A and chromatin to inhibit NF-kB

ABSTRACT: Intracellular pathogens inhibit nuclear factor-κB (NF-κB), the key transcriptional regulator of antimicrobial responses, using incompletely defined mechanisms. NF-κB nuclear localization and gene accessibility is mediated by Ser22-phosphorylated lamin A/C (pSer22-lamin A/C). Here, we report that the obligate intracellular bacterium Orientia tsutsugamushi impairs NF-κB nuclear accumulation by targeting lamin A using a cohort of ankyrin repeat (AR)-containing effectors (Anks) that have a PRANC (pox proteins repeats of ankyrin C-terminal) domain. The Anks’ immunomodulatory capability relies on a hydrophilic peptide that binds lamin A and pSer22-lamin A. Positioning of this peptide in an a-helix between the AR and PRANC domains is functionally essential. O. tsutsugamushi and ectopically expressed Ank1, one of the NF-κB-inhibiting Anks, promote pSer22-lamin A localization to the nucleoplasm. Orientia also alters chromatin to a primarily closed state to limit accessibility at many sites including those regulated by lamin A/pSer22-lamin A along with NF-κB and its coactivator, adapter protein 1. Thus, O. tsutsugamushi synergistically modulates lamin A and chromatin accessibility to counteract NF-κB. These findings reveal a strategy by which an intracellular microbe subverts host immunity, reinforces the regulatory link between lamin A and NF-κB, and indicates that pSer22-lamin A activates NF-κB by increasing chromatin accessibility to it and its coactivators.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307027 | GEO | 2026/04/13

REPOSITORIES: GEO

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Project description:Background: It has been shown that intracellular pathogens hijack DC functions to evade immune defense mechanisms. In this study, we investigated the responses of human monocyte derived DCs to four intracellular bacteria, Tropheryma whipplei, Coxiella burnetii, Brucella abortus and Orientia tsutsugamushi, responsible for human infectious diseases and known to infect myeloid cells. Methods: Whole genome microarrays were assessed to define common and specific transcriptionnal responses to bacterial pathogen. Bacterial pathogen ability to affect DC maturation was assessed by measuring lymphoproliferation and endocytosis as well as phenotypic maturation markers (CD80, CD83, CD86 and HLA-DR) expression. Results: We found that Coxiella burnetii, Orientia tsutsugamushi and Brucella abortus induced DC maturation assessed through decreased endocytosis ability, triggering lymphoproliferation, surface expression of HLA class II molecules and phenotypic changes, whereas Tropheryma whipplei did not induce DC maturation. As revealed by microarray analysis, the response of DCs to these bacteria consisted of a core associated with the maturation of DCs and signatures specific for each pathogen. The core response represented 10% of genes modulated in response to pathogens and consisted of general cellular processes including nucleotide binding, protein transport, cell fraction, protein kinase, cell cycle, mitochondrial membrane and cytoskeleton. The specific transcriptional signature induced by C. burnetii is associated with the communication between innate and adaptive immune cells and DC maturation. B. abortus signature specifically involved arachidonic acid and lipooxygenase pathways and O. tsutsugamushi signature involved type I and type III IFN responses. Conclusion: This study demonstrates that intracellular bacteria use multifaceted pathways to induce DC maturation which may lead to unadapted immune response. The understanding of these pathways may be useful to improve our knowledge of bacterial recognition by the immune system but also intracellular bacterial diseases. IL4/GM-CSF monocyte-derived dendritic cells were stimulated by T. whipplei, B. abortus, C. burnetii, O. tsutsugamushi and LPS during 6 hours. Common and specific signatures were determined by comparison with uninfected DCs. moDCs (5.10^6) were plated in 6 well plates and stimulated with bacteria or LPS for 6 hours, and total RNA was extracted using the RNeasy minikit (Qiagen, adresse CA) and DNase treatment. The Agilent-014850 4X44k Human Whole Genome microarrays (Agilent Technologies, CA) representing 44,000 probes were used as recently described. Reverse transcription, sample labeling and hybridization were performed according to protocols specified by the manufacturer (One-Color Microarray-Based Gene Expression Analysis). Three samples per experimental condition were included in the analysis.

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Orientia tsutsugamushi Ank effectors target lamin A and chromatin to inhibit NF-kB

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