Orientia tsutsugamushi alters the intranuclear balance of cullin-1 and c-MYC to inhibit apoptosis

Infection and Immunity, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

ABSTRACT Cullin-1 (Cul1), a cullin–RING ubiquitin ligase component, represses c-MYC activity in the nucleus. Orientia tsutsugamushi causes potentially fatal rickettsiosis, scrub typhus. The obligate intracellular bacterium encodes an arsenal of ankyrin repeat-containing effectors (Anks), many which carry eukaryotic-like F-box motif that binds Cul1. O. reduces Cul1 levels This phenomenon is not due to alteration neddylation but bacterial burden- and protein synthesis-dependent. Five 11 Anks capable binding (Ank1, Ank5, Ank6, Ank9, Ank17) sequester it cytoplasm when each ectopically expressed. Ank1 Ank6 proteins with alanine substitutions their F-boxes render them unable bind cannot exclude from Coincident reduction nuclei -infected cells, nuclear are elevated, target genes differentially Several these regulate apoptosis. resistance cells staurosporine-induced apoptosis recapitulated uninfected expressing or alanine-substituted versions thereof Other F-box-containing nucleus also fail confer Overall, modulates Cul1:c-MYC intranuclear balance as anti-apoptotic strategy functionally linked subset its Anks.

Language: Английский

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Moonlighting in Rickettsiales: Expanding Virulence Landscape

Tropical Medicine and Infectious Disease, Journal Year: 2022, Volume and Issue: 7(2), P. 32 - 32

Published: Feb. 19, 2022

The order Rickettsiales includes species that cause a range of human diseases such as granulocytic anaplasmosis (

Language: Английский

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Orientia and Rickettsia: different flowers from the same garden

Current Opinion in Microbiology, Journal Year: 2023, Volume and Issue: 74, P. 102318 - 102318

Published: April 18, 2023

Recent discoveries of basal extracellular Rickettsiales have illuminated divergent evolutionary paths to host dependency in later-evolving lineages. Family Rickettsiaceae, primarily comprised numerous protist- and invertebrate-associated species, also includes human pathogens from two genera, Orientia Rickettsia. Once considered sister taxa, these bacteria form distinct lineages with newly appreciated lifestyles morphological traits. Contrasting other rickettsial Anaplasmataceae, Rickettsia species do not reside host-derived vacuoles lack glycolytic potential. With only a few described mechanisms, strategies for commandeering glycolysis support cytosolic growth remain be discovered. While regulatory systems this unique mode intracellular parasitism are unclear, conjugative transposons provide insights that critical determining how obligate overtake eukaryotic cytosol.

Language: Английский

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The Obligate Intracellular Bacterial Pathogen Anaplasma phagocytophilum Exploits Host Cell Multivesicular Body Biogenesis for Proliferation and Dissemination

mBio, Journal Year: 2022, Volume and Issue: 13(6)

Published: Nov. 21, 2022

Anaplasma phagocytophilum causes granulocytic anaplasmosis, a globally emerging zoonosis that can be severe, even fatal, and for which antibiotic treatment options are limited. A. lives in an endosomal-like compartment interfaces with multiple organelles from it must ultimately exit to spread within the host. How bacterium accomplishes these tasks is poorly understood.

Language: Английский

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Orientia tsutsugamushi: comprehensive analysis of the mobilome of a highly fragmented and repetitive genome reveals the capacity for ongoing lateral gene transfer in an obligate intracellular bacterium

mSphere, Journal Year: 2023, Volume and Issue: 8(6)

Published: Oct. 18, 2023

Obligate intracellular bacteria, or those only capable of growth inside other living cells, have limited opportunities for horizontal gene transfer with microbes due to their isolated replicative niche. The human pathogen Ot, an obligate bacterium causing scrub typhus, encodes unusually high copy number a ~40 mobile genetic element that typically facilitates across microbes. This proliferated is heavily degraded in Ot and previously assumed be inactive. Here, we conducted detailed analysis this eight strains discovered two at least one intact copy. implies the still moving populations suggests genome may even more dynamic than appreciated. Our work raises questions about microbial evolution sounds alarm gene-based efforts focused on diagnosing combatting typhus.

Language: Английский

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Orientia tsutsugamushi Ank5 promotes NLRC5 cytoplasmic retention and degradation to inhibit MHC class I expression

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 14, 2024

How intracellular bacteria subvert the major histocompatibility complex (MHC) class I pathway is poorly understood. Here, we show that obligate bacterium Orientia tsutsugamushi uses its effector protein, Ank5, to inhibit nuclear translocation of MHC gene transactivator, NLRC5, and orchestrate proteasomal degradation. Ank5 a tyrosine in fourth ankyrin repeat bind NLRC5 N-terminus while F-box directs host SCF ubiquitination leucine-rich region dictates susceptibility Orientia- Ank5-mediated The ability O. strains degrade correlates with ank5 genomic carriage. Ectopically expressed can but not protects transactivator during infection. Thus, an immunoevasin bipartite architecture rid cells reduce surface molecules. This study offers insight into how pathogens impair expression.

Language: Английский

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Comparative virulence analysis of seven diverse strains ofOrientia tsutsugamushireveals a multifaceted and complex interplay of virulence factors responsible for disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

Abstract Orientia tsutsugamushi is an obligate intracellular bacterium found in Leptotrombidium mites that causes the human disease scrub typhus. A distinguishing feature of O. its extensive strain diversity, yet differences virulence between strains are not well defined nor understood. We sought to determine bacterial drivers pathogenicity by comparing murine infections using seven combined with epidemiological data rank each terms relative virulence. Murine cytokine expression revealed two most virulent strains, Ikeda and Kato, induced higher levels IL-6, IL-10, IFN-γ MCP-1 than other consistent increased these cytokines severe typhus patients. identify mechanistic basis observed differential their genomes, vitro growth properties cytokine/chemokine induction host cells. there was no single gene or group correlated virulence, clear pattern rate predicted disease. However, microscopy-based analysis infection cycle only fully avirulent our study, TA686, differed from all subcellular localisation surface protein ScaC. conclude distributed throughout genome, likely large varying arsenal effector proteins encoded different interact complex ways induce differing immune responses thus outcomes mammalian hosts. Author Summary Scrub a vector-borne caused tsutsugmushi spread mites. There numerous this some causing more humans others, do cause any illness at all. The factors driving understood, gaining insight into them could aid vaccine development help predict severity new isolates. To better typhus, we carried out experiments which compared diverse for animals. measured ability mice, so reliably classify as model. then analysed various genomic biological aspects markers both mice humans. report here factor predicts whether will be pathogenic not, but process resulting activity multiple genes working together drive host, either clearance bacteria escalating Future work exploring relationship disentangle detail.

Language: Английский

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Orientia tsutsugamushi Modulates RIPK3 Cellular Levels but Does Not Inhibit Necroptosis

Pathogens, Journal Year: 2025, Volume and Issue: 14(5), P. 478 - 478

Published: May 14, 2025

Scrub typhus is an emerging chigger-borne disease caused by the obligate intracellular bacterium Orientia tsutsugamushi. Necroptosis a form of programmed cell death (PCD) mediated RIPK3 (serine/threonine kinase receptor interacting protein 3) and its downstream effector MLKL (mixed-lineage domain-like). While O. tsutsugamushi modulates apoptosis, another PCD, interplay with necroptosis unknown. Much pathobiology linked to ankyrin repeat (AR)-containing effectors (Anks). Two these, Ank1 Ank6, share similarities cowpox AR protein, vIRD (viral inducer degradation) that prevents necroptosis. Here, we show Ank6 reduce cellular levels although not as robustly mechanistically distinct from vIRD. infection lowers amounts does elicit in endothelial cells. In HeLa cells ectopically expressing RIPK3, fails inhibit phosphorylation well death. colocalization or Listeria monocytogenes, intracytoplasmic pathogen, was observed. Thus, reduces but cannot this PCD pathway once it induced. This study first step toward understanding how relationship between contributes scrub pathogenesis.

Language: Английский

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Wolbachiauses ankyrin repeats to target specific fly proteins

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: May 17, 2025

Arthropods, the most diverse phylum on Earth, are hosts to a plethora of bacterial parasites that secrete various effectors unknown function during infection. The prevalent these is intracellular bacterium Wolbachia pipientis . microbe infects between 40-60% insect species, causes important reproductive manipulations, and limits virus replication in arthropod vectors, becoming promising biocontrol agent. Understanding molecular basis infection Wolbachia- induced phenotypes critical use vector control. These ankyrin repeat proteins (WARPs) represent highly dynamic part pangenome remain thus far, largely uncharacterized. Here, we perform genetic screens identify interactions w Mel WARPs their target host Drosophila melanogaster Our results strong two proteins, WARP434 WARP754, with targets (CG11327 Ptp61F, respectively). Heterologous expression extremely toxic tissues toxicity dependent domain each WARP. Importantly, knockdown alleviates toxicity, confirming WARP/target interactions. Finally, antibodies targeting both show by cells. how manipulates its biology which pathways it will help us divine parasite Earth interacts at level. screen first step towards goal. Molecular drive co-evolutionary arms races pathogens. shape structure enabling immunity or virulence details unfold events illustrates not only co-evolve level but also may characterize poorly understood proteins. earth pipientis, insects harboring symbiont. cells tools uses alter cell used symbiont interface specific mechanisms underlying this host-microbe interaction shed light an symbiont, control populations disease transmission, interact protein contributes

Language: Английский

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Orientia tsutsugamushi OtDUB Is Expressed and Interacts with Adaptor Protein Complexes during Infection

Infection and Immunity, Journal Year: 2022, Volume and Issue: 90(12)

Published: Nov. 14, 2022

Orientia tsutsugamushi is an etiologic agent of scrub typhus, a globally emerging rickettsiosis that can be fatal. The bacterium’s obligate intracellular lifestyle requires its interaction with host eukaryotic cellular pathways.

Language: Английский

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