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

Lynn Soong, Thomas Shelite, Yan Xing, Harica Kodakandla, Yuejin Liang, Brandon Trent, Paulina Horton, Kathryn C. Smith, Zhenyang Zhao, Jiaren Sun, Donald Bouyer, Jiyang Cai

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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-γ, TNF-α, 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.

Original languageEnglish (US)
Article numbere0005765
JournalPLoS Neglected Tropical Diseases
Volume11
Issue number7
DOIs
StatePublished - Jul 24 2017

Fingerprint

Orientia tsutsugamushi
Scrub Typhus
Blood Vessels
Phagocytes
Infection
Brain
Angiopoietins
Staining and Labeling
Occludin
Pattern Recognition Receptors
Meningoencephalitis
Interleukin-13
Tight Junctions
Intercellular Adhesion Molecule-1
Neurologic Manifestations
Gram-Negative Bacteria
Inbred C57BL Mouse
Meningitis
Lectins
Astrocytes

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

Cite this

Type 1-skewed neuroinflammation and vascular damage associated with Orientia tsutsugamushi infection in mice. / Soong, Lynn; Shelite, Thomas; Xing, Yan; Kodakandla, Harica; Liang, Yuejin; Trent, Brandon; Horton, Paulina; Smith, Kathryn C.; Zhao, Zhenyang; Sun, Jiaren; Bouyer, Donald; Cai, Jiyang.

In: PLoS Neglected Tropical Diseases, Vol. 11, No. 7, e0005765, 24.07.2017.

Research output: Contribution to journalArticle

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abstract = "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-γ, TNF-α, 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.",
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AU - Liang, Yuejin

AU - Trent, Brandon

AU - Horton, Paulina

AU - Smith, Kathryn C.

AU - Zhao, Zhenyang

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