ArticlePLoS neglected tropical diseases2020
Polarized lung inflammation and Tie2/angiopoietin-mediated endothelial dysfunction during severe Orientia tsutsugamushi infection.
Article in PLoS neglected tropical diseases, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 33 citations in OpenAlex.
- Nasopharyngeal Swabs forPathogens (Basel, Switzerland) · 2026Article
- A humanized IFN-γ mouse model reveals skin eschar formation, enhanced susceptibility and scrub typhus pathogenesis.PLoS pathogens · 2026Article
- Differential spleen immune signatures and germinal center responses during acute infection withFrontiers in immunology · 2026Article
- Orientia tsutsugamushi modulates p53, the cell cycle, and genotoxicity to maintain its intracellular niche.Nature communications · 2025Article
- Orientia tsutsugamushi Ank5 promotes NLRC5 cytoplasmic retention and degradation to inhibit MHC class I expression.Nature communications · 2024Article
- Canonical notch activation in patients with scrub typhus: association with organ dysfunction and poor outcome.Infection · 2024Article
- Lack of the IFN-γ signal leads to lethal Orientia tsutsugamushi infection in mice with skin eschar lesions.PLoS pathogens · 2024Article
- The Angiopoietin Signaling Pathway Is Involved in Inflammatory Processes in Hospitalized COVID-19 Patients.Microorganisms · 2023Article
- Differential cellular immune responses against Orientia tsutsugamushi Karp and Gilliam strains following acute infection in mice.PLoS neglected tropical diseases · 2023Article
- Intranasal Immunization With Nanoparticles Containing anImmune network · 2023Article
- Alterations in germinal center formation and B cell activation during severe Orientia tsutsugamushi infection in mice.PLoS neglected tropical diseases · 2023Article
- Article
- Host transcriptomic profiling of CD-1 outbred mice with severe clinical outcomes following infection with Orientia tsutsugamushi.PLoS neglected tropical diseases · 2022Article
- CCR7/dendritic cell axis mediates early bacterial dissemination inFrontiers in immunology · 2022Article
- Distinct Role of TNFR1 and TNFR2 in Protective Immunity AgainstFrontiers in immunology · 2022Article
- Orientia tsutsugamushi selectively stimulates the C-type lectin receptor Mincle and type 1-skewed proinflammatory immune responses.PLoS pathogens · 2021Article
- Intranasal Vaccination with Outer-Membrane Protein ofImmune network · 2021Article
- Endothelial Activation inFrontiers in cellular and infection microbiology · 2021Article
- Pattern Recognition Receptors in Innate Immunity to Obligate Intracellular Bacteria.Zoonoses (Shannon, Ireland) · 2021Article
- CCR2 Deficiency Impairs Ly6CFrontiers in immunology · 2021Article
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
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.
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