Open AccessPolarized lung inflammation and Tie2/angiopoietin-mediated endothelial dysfunction during severe Orientia tsutsugamushi infection
Author(s) -
Brandon Trent,
Yuejin Liang,
Yan Xing,
Marisol Esqueda,
Wenyan Yang,
Nam Hyuk Cho,
Hong Il Kim,
So Hyun Kim,
Thomas R. Shelite,
Jiyang Cai,
Jiaren Sun,
Donald H. Bouyer,
Jinjun Liu,
Lynn Soong
Publication year - 2020
Publication title -
plos neglected tropical diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.99
H-Index - 135
eISSN - 1935-2735
pISSN - 1935-2727
DOI - 10.1371/journal.pntd.0007675
Subject(s) - scrub typhus , orientia tsutsugamushi , biology , immunology , inflammation , lung , angiopoietin , angiopoietin receptor , pathology , medicine , angiogenesis , virology , cancer research , vascular endothelial growth factor , vegf receptors
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.