AUTHOR=Kurosu Takeshi , Sakai Yusuke , Ami Yasusi , Shimojima Masayuki , Yoshikawa Tomoki , Fukushi Shuetsu , Nagata Noriyo , Suzuki Tadaki , Ebihara Hideki , Saijo Masayuki TITLE=Mice, myeloid cells, and dengue: a new model for unraveling vascular leakage mysteries JOURNAL=Frontiers in Microbiology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1367672 DOI=10.3389/fmicb.2024.1367672 ISSN=1664-302X 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+Ifnarflox/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+Ifnarflox/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.