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PLoS Negl Trop Dis. 2017 Jul 24;11(7):e0005765. doi: 10.1371/journal.pntd.0005765. eCollection 2017 Jul.

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

Author information

1
Department of Microbiology and Immunology, Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America.
2
Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
3
Department of Internal Medicine/Division of Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, United States of America.
4
Pediatrics Department, People's Hospital of Henan Province, Zheng Zhou, Henan, China.
5
School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
6
Center in Environmental Toxicology, University of Texas Medical Branch, Galveston, Texas, United States of America.
7
Department of Ophthalmology, Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America.

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.

PMID:
28742087
PMCID:
PMC5542690
DOI:
10.1371/journal.pntd.0005765
[Indexed for MEDLINE]
Free PMC Article

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