Differences in Intracellular Fate of Two Spotted Fever Group Rickettsia in Macrophage-Like Cells

Curto, Pedro; Simões, Isaura; Riley, Sean P.; Martínez, Juan José

doi:10.3389/fcimb.2016.00080

Cited by 46 publications

(62 citation statements)

References 51 publications

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“…Monocytes/MΦs play important roles in infection with O. tsutsugamushi and other closely related Rickettsia species [19, 57]. Previous findings [19] are consistent with our observation of an increased accumulation of CD11b + Ly6G - MΦs/monocytes and the close association of IBA-l + phagocytes with Orientia in the lungs at D6 and D9.…”

Section: Discussionsupporting

confidence: 92%

Polarized Lung Inflammation and Tie2/Angiopoietin-Mediated Endothelial Dysfunction during SevereOrientia tsutsugamushiInfection

Trent

Liang

Xing

et al. 2019

Preprint

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27 of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-0435 28 #d Current Address: Department of Physiology, OUHSC, 940 Stanton Young Blvd., Oklahoma 29 City, OK 73104-5042 30 31 32 33 * Corresponding Authors: Jinjun Liu: jupet@163.com; Lynn Soong: lysoong@utmb.edu 34 35 36 Abstract 38Orientia tsutsugamushi infection can cause acute lung injury and high mortality in humans; 39 however, the underlying mechanisms are unclear. Here, we tested a hypothesis that dysregulated 40 pulmonary inflammation and Tie2-mediated endothelial malfunction contribute to lung damage. 41 Using a murine model of lethal O. tsutsugamushi infection, we demonstrated pathological 42 characteristics of vascular activation and tissue damage: 1) a significant increase of ICAM-1, 43 VEGFR2, and angiopoietin-2 (Ang2) proteins in inflamed tissues and lung-derived endothelial 44 cells (EC), 2) a progressive loss of endothelial quiescent and junction proteins (Ang1, VE-45 cadherin/CD144, occuludin), and 3) a profound impairment of Tie2 receptor at the 46 transcriptional and functional levels. In vitro infection of primary human EC cultures and serum 47 52 (CD206 + CD64 + CD11b + Ly6G -) cells. In vitro studies indicated extensive bacterial replication in 53 M2-type, but not M1-type, MΦs, implying the protective and pathogenic roles of M1-skewed 54 responses. This is the first detailed investigation of lung cellular immune responses during acute 55 O. tsutsugamushi infection. It uncovers specific biomarkers for vascular dysfunction and M1-56 skewed inflammatory responses, highlighting future therapeutic research for the control of this 57 neglected tropical disease.58 59 4 Author Summary 60Scrub typhus is a life-threatening disease, infecting an estimated one million people yearly. 61Acute lung injury is the most common clinical observation; however, its pathogenic biomarkers 62 and mechanisms of progression remain unknown. Here, we used a lethal infection mouse model 63 that parallels certain aspects of severe scrub typhus, primary human endothelial cell cultures, and 64 patient sera to define pathogenic biomarkers following Orientia tsutsugamushi infections. We 65 found a significant increase in the levels of endothelial activation/stress markers (angiopoietins 66 and ICAM-1) in infected mouse lungs and in patient sera, but a progressive loss of endothelium-67 specific Tie2 receptor and junction proteins (VE-cadherin), at severe stages of disease. These 68 signs of vasculature disruption positively correlated with the timing and magnitude of 69 recruitment/activation of proinflammatory MΦ subsets in infected lungs. Bacterial growth in 70 vitro was favored in M2-like, but not in M1-like, MΦs. This study, for the first time, reveals 71 endothelial malfunction and dysregulated inflammatory responses, suggesting potential 72 therapeutic targets to ameliorate tissue damage and pathogenesis. 73 74 Scrub typhus is a febrile and potentially lethal illness that infects an estimated one million 75 individuals per year [1]. The disease is ca...

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Section: Discussionsupporting

confidence: 92%

Polarized Lung Inflammation and Tie2/Angiopoietin-Mediated Endothelial Dysfunction during SevereOrientia tsutsugamushiInfection

Trent

Liang

Xing

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Monocytes/MFs play important roles in infection with O. tsutsugamushi and other closely related Rickettsia species [22,59]. Previous findings [22] are consistent with our observation of an increased accumulation of CD64 + CD11b + Ly6G -MFs/monocytes and the close association of IBA-l + phagocytes with Orientia in the lungs at D6 and D9.…”

Section: Plos Neglected Tropical Diseasessupporting

confidence: 91%

Polarized lung inflammation and Tie2/angiopoietin-mediated endothelial dysfunction during severe Orientia tsutsugamushi infection

et al. 2020

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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 PLOS NEGLECTED TROPICAL DISEASES

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“…Some Rickettsia species can be transmitted to humans and cause diseases, including spotted fever and typhus 4,5 . During infection of mammals, Rickettsia species primarily target vascular endothelial cells, although they can reside in a wide variety of cell types, including dendritic cells 6 and macrophages 7,8 .…”

Section: Introductionmentioning

confidence: 99%

Evasion of autophagy mediated by Rickettsia surface protein OmpB is critical for virulence

et al. 2019

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Rickettsia are obligate intracellular bacteria that evade antimicrobial autophagy in the host cell cytosol by unknown mechanisms. Other cytosolic pathogens block different steps of autophagy targeting, including the initial step of polyubiquitin coat formation. One mechanism of evasion is to mobilize actin to the bacterial surface. Here, we show that actin mobilization is insufficient to block autophagy recognition of the pathogen Rickettsia parkeri. Instead, R. parkeri employs outer membrane protein B (OmpB) to block ubiquitylation of bacterial surface proteins, including OmpA, and subsequent recognition by autophagy receptors. OmpB is also required for the formation of a capsule-like layer. Although OmpB is dispensable for bacterial growth in endothelial cells, it is essential for R. parkeri to block autophagy in macrophages and to colonize mice because of its ability to promote autophagy evasion in immune cells. Our results indicate that OmpB acts as a protective shield to obstruct autophagy recognition, revealing a distinctive bacterial mechanism to evade antimicrobial autophagy.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Differences in Intracellular Fate of Two Spotted Fever Group Rickettsia in Macrophage-Like Cells

Cited by 46 publications

References 51 publications

Polarized Lung Inflammation and Tie2/Angiopoietin-Mediated Endothelial Dysfunction during SevereOrientia tsutsugamushiInfection

Polarized Lung Inflammation and Tie2/Angiopoietin-Mediated Endothelial Dysfunction during SevereOrientia tsutsugamushiInfection

Polarized lung inflammation and Tie2/angiopoietin-mediated endothelial dysfunction during severe Orientia tsutsugamushi infection

Evasion of autophagy mediated by Rickettsia surface protein OmpB is critical for virulence

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