Dataset Information

Mice, myeloid cells, and dengue: a new model for unraveling vascular leakage mysteries.

ABSTRACT:

Introduction

Severe dengue is thought to be caused by an excessive host immune response.

Methods

To study the pathogenesis of severe dengue, we developed a novel model using LysM Cre⁺Ifnar^flox/flox mice carrying depleted Ifnar expression only in subsets of murine myeloid cells.

Results

Although dengue virus (DENV) clinical isolates were not virulent in LysM Cre⁺Ifnar^flox/flox mice, mouse-adapted DV1-5P7Sp and DV3P12/08P4Bm, which were obtained by passaging the spleen or bone marrow of mice, demonstrated 100% lethality with severe vascular leakage in the liver and small intestine. DV1-5P7Sp and DV3P12/08P4Bm harbored five and seven amino acid substitutions, respectively. Infection also induced neutrophil infiltration in the small intestine, and increased expression of IL-6 and MMP-8 and blockade of TNF-α signaling protected the mice, as demonstrated in a previous severe dengue mouse model using C57/BL6 mice lacking both IFN-α/β and IFN-γ receptors. Notably, the new models with DV1-5P7Sp and DV3P12/08P4Bm showed an increased proliferative capacity of the adapted viruses in the thymus and bone marrow.

Discussion

These observations suggest that myeloid cell infection is sufficient to trigger cytokine storm-induced vascular leakage. This model can refine the factors involved in the pathology of severe dengue leading to vascular leakage.

SUBMITTER: Kurosu T

PROVIDER: S-EPMC10972876 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Publications

Mice, myeloid cells, and dengue: a new model for unraveling vascular leakage mysteries.

Kurosu Takeshi T Sakai Yusuke Y Ami Yasusi Y Shimojima Masayuki M Yoshikawa Tomoki T Fukushi Shuetsu S Nagata Noriyo N Suzuki Tadaki T Ebihara Hideki H Saijo Masayuki M

Frontiers in microbiology 20240314

<h4>Introduction</h4>Severe dengue is thought to be caused by an excessive host immune response.<h4>Methods</h4>To study the pathogenesis of severe dengue, we developed a novel model using LysM Cre<sup>+</sup><i>Ifnar</i><sup>flox/flox</sup> mice carrying depleted <i>Ifnar</i> expression only in subsets of murine myeloid cells.<h4>Results</h4>Although dengue virus (DENV) clinical isolates were not virulent in LysM Cre<sup>+</sup><i>Ifnar</i><sup>flox/flox</sup> mice, mouse-adapted DV1-5P7Sp and ...[more]

PMID: 38550855

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Project description:Dengue is a major health problem in tropical and subtropical regions. Some patients develop a severe form of dengue, called dengue hemorrhagic fever, which can be fatal. Severe dengue is associated with a transient increase in vascular permeability. A cytokine storm is thought to be the cause of the vascular leakage. Although there are various research reports on the pathogenic mechanism, the complete pathological process remains poorly understood. We previously reported that dengue virus (DENV) type 3 P12/08 strain caused a lethal systemic infection and severe vascular leakage in interferon (IFN)-α/β and γ receptor knockout mice (IFN-α/β/γRKO mice), and that blockade of TNF-α signaling protected mice. Here, we performed transcriptome analysis of liver and small intestine samples collected chronologically from P12/08-infected IFN-α/β/γRKO mice in the presence/absence of blockade of TNF-α signaling and evaluated the cytokine and effector-level events. Blockade of TNF-α signaling mainly protected the small intestine but not the liver. Infection induced the selective expansion of IL-17A-producing Vγ4 and Vγ6 T cell receptor (TCR) γδ T cells in the small intestine, and IL-17A, together with TNF-α, played a critical role in the transition to severe disease via the induction of inflammatory cytokines such as TNF-α, IL-1β, and particularly the excess production of IL-6. Infection also induced the infiltration of neutrophils, as well as neutrophil collagenase/matrix metalloprotease 8 production. Blockade of IL-17A signaling reduced mortality and suppressed the expression of most of these cytokines, including TNF-α, indicating that IL-17A and TNF-α synergistically enhance cytokine expression. Blockade of IL-17A prevented nuclear translocation of NF-κB p65 in stroma-like cells and epithelial cells in the small intestine but only partially prevented recruitment of immune cells to the small intestine. This study provides an overall picture of the pathogenesis of infection in individual mice at the cytokine and effector levels.

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Dataset Information

Mice, myeloid cells, and dengue: a new model for unraveling vascular leakage mysteries.

Introduction

Methods

Results

Discussion

Publications

Mice, myeloid cells, and dengue: a new model for unraveling vascular leakage mysteries.

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