Abstract
Orientia tsutsugamushi infection can cause acute lung injury and high mortality in humans; however, the underlying mechanisms are unclear. Here, we tested a hypothesis that dysregulated pulmonary inflammation and Tie2-mediated endothelial malfunction contribute to lung damage. Using a murine model of lethal O. tsutsugamushi infection, we demonstrated pathological characteristics of vascular activation and tissue damage: 1) a significant increase of ICAM-1 and angiopoietin-2 (Ang2) proteins in inflamed tissues and lung-derived endothelial cells (EC), 2) a progressive loss of endothelial quiescent and junction proteins (Ang1, VE-cadherin/CD144, occuludin), and 3) a profound impairment of Tie2 receptor at the transcriptional and functional levels. In vitro infection of primary human EC cultures and serum Ang2 proteins in scrub typhus patients support our animal studies, implying endothelial dysfunction in severe scrub typhus. Flow cytometric analyses of lung-recovered cells further revealed that pulmonary macrophages (MΦ) were polarized toward an M1-like phenotype (CD80+CD64+CD11b+Ly6G-) during the onset of disease and prior to host death, which correlated with the significant loss of CD31+CD45- ECs and M2-like (CD206+CD64+CD11b+Ly6G-) cells. In vitro studies indicated extensive bacterial replication in M2-type, but not M1-type, MΦs, implying the protective and pathogenic roles of M1-skewed responses. This is the first detailed investigation of lung cellular immune responses during acute O. tsutsugamushi infection. It uncovers specific biomarkers for vascular dysfunction and M1-skewed inflammatory responses, highlighting future therapeutic research for the control of this neglected tropical disease.
Highlights
Scrub typhus is a febrile and potentially lethal illness that infects an estimated one million individuals per year [1]
We found a significant increase in the levels of endothelial activation/stress markers in infected mouse lungs and patient sera, but a progressive loss of endothelium-specific Tie2 receptor and junction proteins (VE-cadherin), at severe stages of disease
Pulmonary endothelial cells (ECs) activation and tight junction disruption during infection in mice Given that the lung is a major site of O. tsutsugamushi infection in humans and animal models [6, 35] and that EC activation and disruption of vascular barrier integrity are principal steps for acute lung injury in sepsis and pneumonia models [38], we sought to investigate pulmonary EC activation in C57BL/6 mice following i.v. inoculation with a lethal dose of O. tsutsugamushi Karp (~1.325×106 viable bacteria in 200 μl of PBS)
Summary
Scrub typhus is a febrile and potentially lethal illness that infects an estimated one million individuals per year [1]. Scrub typhus is reported to cause a substantial proportion (approximately 15–23%) of reported febrile illness [3, 4]. Scrub typhus can manifest as interstitial pneumonia, myocardial and hepatic inflammation, and meningoencephalitis. Mild interstitial pneumonitis is typically the extent of pulmonary involvement during self-resolving or promptly treated scrub typhus. Acute respiratory distress syndrome and lung damage are associated with high mortality and present in 6.75–25% of scrub typhus patients [5, 7]; there is no detailed investigation of the underlying mechanisms responsible for pulmonary endothelial dysfunction and inflammation
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