Orientia tsutsugamushi modulates cellular levels of NF-κB inhibitor p105.
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 tsuts...
Published in: | PLOS Neglected Tropical Diseases |
---|---|
Main Authors: | , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
Public Library of Science (PLoS)
2021
|
Subjects: | |
Online Access: | https://doi.org/10.1371/journal.pntd.0009339 https://doaj.org/article/1f62bf2325094545a226f27388de3e84 |
id |
ftdoajarticles:oai:doaj.org/article:1f62bf2325094545a226f27388de3e84 |
---|---|
record_format |
openpolar |
spelling |
ftdoajarticles:oai:doaj.org/article:1f62bf2325094545a226f27388de3e84 2023-05-15T15:16:54+02:00 Orientia tsutsugamushi modulates cellular levels of NF-κB inhibitor p105. Tanaporn Wangsanut Katelynn R Brann Haley E Adcox Jason A Carlyon 2021-04-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0009339 https://doaj.org/article/1f62bf2325094545a226f27388de3e84 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0009339 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009339 https://doaj.org/article/1f62bf2325094545a226f27388de3e84 PLoS Neglected Tropical Diseases, Vol 15, Iss 4, p e0009339 (2021) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2021 ftdoajarticles https://doi.org/10.1371/journal.pntd.0009339 2022-12-31T14:48:54Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 15 4 e0009339 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Tanaporn Wangsanut Katelynn R Brann Haley E Adcox Jason A Carlyon Orientia tsutsugamushi modulates cellular levels of NF-κB inhibitor p105. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Tanaporn Wangsanut Katelynn R Brann Haley E Adcox Jason A Carlyon |
author_facet |
Tanaporn Wangsanut Katelynn R Brann Haley E Adcox Jason A Carlyon |
author_sort |
Tanaporn Wangsanut |
title |
Orientia tsutsugamushi modulates cellular levels of NF-κB inhibitor p105. |
title_short |
Orientia tsutsugamushi modulates cellular levels of NF-κB inhibitor p105. |
title_full |
Orientia tsutsugamushi modulates cellular levels of NF-κB inhibitor p105. |
title_fullStr |
Orientia tsutsugamushi modulates cellular levels of NF-κB inhibitor p105. |
title_full_unstemmed |
Orientia tsutsugamushi modulates cellular levels of NF-κB inhibitor p105. |
title_sort |
orientia tsutsugamushi modulates cellular levels of nf-κb inhibitor p105. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2021 |
url |
https://doi.org/10.1371/journal.pntd.0009339 https://doaj.org/article/1f62bf2325094545a226f27388de3e84 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 15, Iss 4, p e0009339 (2021) |
op_relation |
https://doi.org/10.1371/journal.pntd.0009339 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009339 https://doaj.org/article/1f62bf2325094545a226f27388de3e84 |
op_doi |
https://doi.org/10.1371/journal.pntd.0009339 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
15 |
container_issue |
4 |
container_start_page |
e0009339 |
_version_ |
1766347196621389824 |