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Type 1-skewed neuroinflammation and vascular damage associated with Orientia tsutsugamushi infection in mice.

Abstract Scrub typhus is a life-threatening disease, due to infection with O. tsutsugamushi, a Gram-negative bacterium that preferentially replicates in endothelial cells and professional phagocytes. Meningoencephalitis has been reported in scrub typhus patients and experimentally-infected animals; however, the neurological manifestation and its underlying mechanisms remain poorly understood. To address this issue, we focused on Orientia tsutsugamushi Karp strain (OtK), and examined host responses in the brain during lethal versus self-healing scrub typhus disease in our newly established murine models.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos neglected tropical diseases
Publication Year Start




PMID- 28742087
OWN - NLM
STAT- MEDLINE
DA  - 20170725
DCOM- 20170810
LR  - 20170810
IS  - 1935-2735 (Electronic)
IS  - 1935-2727 (Linking)
VI  - 11
IP  - 7
DP  - 2017 Jul
TI  - Type 1-skewed neuroinflammation and vascular damage associated with Orientia
      tsutsugamushi infection in mice.
PG  - e0005765
LID - 10.1371/journal.pntd.0005765 [doi]
AB  - BACKGROUND: Scrub typhus is a life-threatening disease, due to infection with O. 
      tsutsugamushi, a Gram-negative bacterium that preferentially replicates in
      endothelial cells and professional phagocytes. Meningoencephalitis has been
      reported in scrub typhus patients and experimentally-infected animals; however,
      the neurological manifestation and its underlying mechanisms remain poorly
      understood. To address this issue, we focused on Orientia tsutsugamushi Karp
      strain (OtK), and examined host responses in the brain during lethal versus
      self-healing scrub typhus disease in our newly established murine models.
      PRINCIPLE FINDINGS: Following inoculation with a lethal dose of OtK, mice had a
      significant increase in brain transcripts related to pathogen-pattern recognition
      receptors (TLR2, TLR4, TLR9), type-1 responses (IFN-gamma, TNF-alpha, CXCL9,
      CXCR3), and endothelial stress/damage such as angiopoietins, but a rapid
      down-regulation of Tie2. Sublethal infection displayed similar trends, implying
      the development of type 1-skewed proinflammatory responses in infected brains,
      independent of time and disease outcomes. Focal hemorrhagic lesions and
      meningitis were evident in both infection groups, but pathological changes were
      more diffuse and frequent in lethal infection. At 6-10 days of lethal infection, 
      the cortex and cerebellum sections had increased ICAM-1-positive staining in
      vascular cells, as well as increased detection of CD45+ leukocytes, CD3+ T cells,
      IBA1+ phagocytes, and GFAP+ astrocytes, but a marked loss of occludin-positive
      tight junction staining, implying progressive endothelial activation/damage and
      cellular recruitment in inflamed brains. Orientia were sparse in the brains, but 
      readily detectable within lectin+ vascular and IBA-1+ phagocytic cells. These CNS
      alterations were consistent with type 1-skewed, IL-13-suppressed responses in
      lethally-infected mouse lungs. SIGNIFICANCE: This is the first report of type
      1-skewed neuroinflammation and cellular activation, accompanied with vascular
      activation/damage, during OtK infection in C57BL/6 mice. This study not only
      enhances our understanding of the pathophysiological mechanisms of scrub typhus, 
      but also correlates the impact of immune and vascular dysfunction on disease
      pathogenesis.
FAU - Soong, Lynn
AU  - Soong L
AD  - Department of Microbiology and Immunology, Institute of Human Infections and
      Immunity, University of Texas Medical Branch, Galveston, Texas, United States of 
      America.
AD  - Department of Pathology, University of Texas Medical Branch, Galveston, Texas,
      United States of America.
FAU - Shelite, Thomas R
AU  - Shelite TR
AUID- ORCID: http://orcid.org/0000-0001-6686-6032
AD  - Department of Microbiology and Immunology, Institute of Human Infections and
      Immunity, University of Texas Medical Branch, Galveston, Texas, United States of 
      America.
AD  - Department of Internal Medicine/Division of Infectious Diseases, University of
      Texas Medical Branch, Galveston, Texas, United States of America.
FAU - Xing, Yan
AU  - Xing Y
AD  - Department of Microbiology and Immunology, Institute of Human Infections and
      Immunity, University of Texas Medical Branch, Galveston, Texas, United States of 
      America.
AD  - Pediatrics Department, People's Hospital of Henan Province, Zheng Zhou, Henan,
      China.
FAU - Kodakandla, Harica
AU  - Kodakandla H
AD  - School of Medicine, University of Texas Medical Branch, Galveston, Texas, United 
      States of America.
FAU - Liang, Yuejin
AU  - Liang Y
AD  - Department of Microbiology and Immunology, Institute of Human Infections and
      Immunity, University of Texas Medical Branch, Galveston, Texas, United States of 
      America.
FAU - Trent, Brandon J
AU  - Trent BJ
AD  - Department of Pathology, University of Texas Medical Branch, Galveston, Texas,
      United States of America.
FAU - Horton, Paulina
AU  - Horton P
AD  - Department of Microbiology and Immunology, Institute of Human Infections and
      Immunity, University of Texas Medical Branch, Galveston, Texas, United States of 
      America.
FAU - Smith, Kathryn C
AU  - Smith KC
AD  - Center in Environmental Toxicology, University of Texas Medical Branch,
      Galveston, Texas, United States of America.
FAU - Zhao, Zhenyang
AU  - Zhao Z
AD  - Department of Ophthalmology, Institute of Human Infections and Immunity,
      University of Texas Medical Branch, Galveston, Texas, United States of America.
FAU - Sun, Jiaren
AU  - Sun J
AD  - Department of Microbiology and Immunology, Institute of Human Infections and
      Immunity, University of Texas Medical Branch, Galveston, Texas, United States of 
      America.
AD  - Department of Pathology, University of Texas Medical Branch, Galveston, Texas,
      United States of America.
FAU - Bouyer, Donald H
AU  - Bouyer DH
AD  - Department of Pathology, University of Texas Medical Branch, Galveston, Texas,
      United States of America.
FAU - Cai, Jiyang
AU  - Cai J
AD  - Department of Ophthalmology, Institute of Human Infections and Immunity,
      University of Texas Medical Branch, Galveston, Texas, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20170724
PL  - United States
TA  - PLoS Negl Trop Dis
JT  - PLoS neglected tropical diseases
JID - 101291488
RN  - 0 (Cytokines)
SB  - IM
MH  - Animals
MH  - Brain/immunology/*pathology
MH  - Cytokines/analysis
MH  - Disease Models, Animal
MH  - Down-Regulation
MH  - Female
MH  - Humans
MH  - Inflammation
MH  - Lung/pathology
MH  - Meningoencephalitis/microbiology/*physiopathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Orientia tsutsugamushi
MH  - Scrub Typhus/*complications/*pathology
EDAT- 2017/07/26 06:00
MHDA- 2017/08/11 06:00
CRDT- 2017/07/26 06:00
PHST- 2017/05/23 [received]
PHST- 2017/06/30 [accepted]
PHST- 2017/08/03 [revised]
AID - 10.1371/journal.pntd.0005765 [doi]
AID - PNTD-D-17-00837 [pii]
PST - epublish
SO  - PLoS Negl Trop Dis. 2017 Jul 24;11(7):e0005765. doi:
      10.1371/journal.pntd.0005765. eCollection 2017 Jul.