Orientia tsutsugamushi modulates cellular levels of NF-κB inhibitor p105.
Active Transport, Cell Nucleus
Bacterial Proteins
/ chemistry
HeLa Cells
Host-Pathogen Interactions
/ genetics
Humans
NF-KappaB Inhibitor alpha
/ metabolism
NF-kappa B p50 Subunit
/ metabolism
Orientia tsutsugamushi
/ immunology
Scrub Typhus
/ immunology
Transcription Factor RelA
/ metabolism
Transcriptional Activation
Tumor Necrosis Factor-alpha
/ metabolism
Virulence
/ genetics
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
19
06
2020
accepted:
29
03
2021
revised:
27
04
2021
pubmed:
16
4
2021
medline:
28
7
2021
entrez:
15
4
2021
Statut:
epublish
Résumé
Scrub typhus is a neglected tropical disease that threatens more than one billion people. If antibiotic therapy is delayed, often due to mis- or late diagnosis, the case fatality rate can increase considerably. Scrub typhus is caused by the obligate intracellular bacterium, Orientia tsutsugamushi, which invades phagocytes and endothelial cells in vivo and diverse tissue culture cell types in vitro. The ability of O. tsutsugamushi to replicate in the cytoplasm indicates that it has evolved to counter eukaryotic host cell immune defense mechanisms. The transcription factor, NF-κB, is a tightly regulated initiator of proinflammatory and antimicrobial responses. Typically, the inhibitory proteins p105 and IκBα sequester the NF-κB p50:p65 heterodimer in the cytoplasm. Canonical activation of NF-κB via TNFα involves IKKβ-mediated serine phosphorylation of IκBα and p105, which leads to their degradation and enables NF-κB nuclear translocation. A portion of p105 is also processed into p50. O. tsutsugamushi impairs NF-κB translocation into the nucleus, but how it does so is incompletely defined. Western blot, densitometry, and quantitative RT-PCR analyses of O. tsutsugamushi infected host cells were used to determine if the pathogen's ability to inhibit NF-κB is linked to modulation of p105. Results demonstrate that p105 levels are elevated several-fold in O. tsutsugamushi infected HeLa and RF/6A cells with only a nominal increase in p50. The O. tsutsugamushi-stimulated increase in p105 is bacterial dose- and protein synthesis-dependent, but does not occur at the level of host cell transcription. While TNFα-induced phosphorylation of p105 serine 932 proceeds unhindered in infected cells, p105 levels remain elevated and NF-κB p65 is retained in the cytoplasm. O. tsutsugamushi specifically stabilizes p105 to inhibit the canonical NF-κB pathway, which advances understanding of how it counters host immunity to establish infection.
Sections du résumé
BACKGROUND
Scrub typhus is a neglected tropical disease that threatens more than one billion people. If antibiotic therapy is delayed, often due to mis- or late diagnosis, the case fatality rate can increase considerably. Scrub typhus is caused by the obligate intracellular bacterium, Orientia tsutsugamushi, which invades phagocytes and endothelial cells in vivo and diverse tissue culture cell types in vitro. The ability of O. tsutsugamushi to replicate in the cytoplasm indicates that it has evolved to counter eukaryotic host cell immune defense mechanisms. The transcription factor, NF-κB, is a tightly regulated initiator of proinflammatory and antimicrobial responses. Typically, the inhibitory proteins p105 and IκBα sequester the NF-κB p50:p65 heterodimer in the cytoplasm. Canonical activation of NF-κB via TNFα involves IKKβ-mediated serine phosphorylation of IκBα and p105, which leads to their degradation and enables NF-κB nuclear translocation. A portion of p105 is also processed into p50. O. tsutsugamushi impairs NF-κB translocation into the nucleus, but how it does so is incompletely defined.
PRINCIPAL FINDINGS
Western blot, densitometry, and quantitative RT-PCR analyses of O. tsutsugamushi infected host cells were used to determine if the pathogen's ability to inhibit NF-κB is linked to modulation of p105. Results demonstrate that p105 levels are elevated several-fold in O. tsutsugamushi infected HeLa and RF/6A cells with only a nominal increase in p50. The O. tsutsugamushi-stimulated increase in p105 is bacterial dose- and protein synthesis-dependent, but does not occur at the level of host cell transcription. While TNFα-induced phosphorylation of p105 serine 932 proceeds unhindered in infected cells, p105 levels remain elevated and NF-κB p65 is retained in the cytoplasm.
CONCLUSIONS
O. tsutsugamushi specifically stabilizes p105 to inhibit the canonical NF-κB pathway, which advances understanding of how it counters host immunity to establish infection.
Identifiants
pubmed: 33857149
doi: 10.1371/journal.pntd.0009339
pii: PNTD-D-20-01099
pmc: PMC8078813
doi:
Substances chimiques
Bacterial Proteins
0
NF-kappa B p50 Subunit
0
NFKB1 protein, human
0
NFKBIA protein, human
0
RELA protein, human
0
TNF protein, human
0
Transcription Factor RelA
0
Tumor Necrosis Factor-alpha
0
NF-KappaB Inhibitor alpha
139874-52-5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0009339Subventions
Organisme : NIAID NIH HHS
ID : R01 AI123346
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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