In:
The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1_Supplement ( 2018-05-01), p. 117.4-117.4
Abstract:
We recently established murine Orientia tsutsugamushi infection models, which mimic immunological features of human scrub typhus. A hallmark of lethal Orientia infection is Th1-skewed, but Th2-impaired, immune responses, accompanied by endothelial dysfunction and multi-organ failure. Notably, while tissue bacterial loads peak at D6 (disease onset) in mice, lung neutrophil and CD8 T cell influx/activation reach peaks at D10 (prior to host death). We proposed a two-stage mechanism for disease pathogenesis: 1) Orientia replication in phagocytes and endothelial cells (EC) triggers inflammatory responses and host defense machinery; 2) infection-mediated release of DAMP molecules further exacerbates vascular damage, even after the control of bacterial replication. This hypothesis was supported by WB, qRT-PCR, and immunofluorescent co-staining of bacteria with leukocyte/EC/platelet-specific markers. During infection, progressive loss of vasculature and tight junctions (occludin, VE-cad, lectin positivity), vascular malfunction (reduced angiopoietin-1, Tie2, pTie2), and reduced CD41+ platelets in the lungs were positively linked to influx/activation of neutrophils and CD8 T cells, rather than bacterial loads. Immune dysregulation mechanisms were further examined by using infected human EC cultures, patient sera, IL-33−/− mice, and mouse macrophages/neutrophils. While Orientia infection can directly alter the angiopoietin/Tie2 axis in EC, endogenous IL-33/IL-36-like DAMPs contribute to vascular and tissue damage at the late stages. Our studies provide new insights into infection- vs. immune-mediated dysregulation and prognostic biomarkers, which will help the control of this neglected tropical disease.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.200.Supp.117.4
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2018
detail.hit.zdb_id:
1475085-5
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