Abstract
BackgroundScrub 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 findingsFollowing 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.SignificanceThis 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.
Highlights
Orientia tsutsugamushi is the etiological agent for scrub typhus, a human disease highly endemic in the “tsutsugamushi triangle” that expands a broad geographic region in Southeast Asia
Meningoencephalitis has been reported in scrub typhus patients and in experimentally infected animals; the neurological manifestation and its underlying mechanisms remain poorly understood
We found no major changes at day 2, but day 6 samples showed significant increase for a panel of genes related to pattern-recognition receptors (TLR2, TLR4, TLR9), type-1 responses (IFN-γ, TNF-α, CXCL9, CXCR3), and endothelial stress or damage such as endothelial nitric oxide synthase, Ang2 and Ang2/1 ratio, respectively (Fig 1)
Summary
Orientia tsutsugamushi is the etiological agent for scrub typhus, a human disease highly endemic in the “tsutsugamushi triangle” that expands a broad geographic region in Southeast Asia. The incidence of scrub typhus cases has been increasing in recent years, and new cases are reported in other geographic areas, including Africa and South America [1] While antibiotics such as doxycycline and ciprofloxacin are known to be effective for treatment, missed or delayed diagnosis and persistent infection are major issues, among others, for this neglected tropical disease [2]. Meningoencephalitis has been reported in scrub typhus patients and experimentallyinfected animals; 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.
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