Chimeric flavivirus causes vascular leakage and bone marrow suppression in a mouse model

Kurosu, Takeshi; Hanabara, Keiko; Asai, Ayumu; Pambudi, Sabar; Phanthanawiboon, Supranee; Omokoko, Magot Diata; Sakai, Yusuke; Suzuki, Tadaki; Ikuta, Kazuyoshi

doi:10.1016/j.bbrc.2023.04.003

Cited by 1 publication

(2 citation statements)

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“…MMP-8 was suspected to be the most important effector that leads to vascular leakage because it was found to be increased commonly in the liver and small intestine of DV3P12/08-infected IFN-α/β/γR KO mice ( Kurosu et al, 2023a ). Neutrophils are considered a major source of MMP-8.…”

Section: Resultsmentioning

confidence: 99%

“… Sarathy et al (2015) reported a model using the DENV-3 C0360/94 strain in AG129 mice. Furthermore, we reported another model using the DENV-3 P12/08 (DV3P12/08) clinical isolate in C57/BL6 mice lacking IFN-α/β and IFN-γ receptors (IFN-α/β/γR KO mice) ( Phanthanawiboon et al, 2016 ; Kurosu et al, 2023b ), as well as a model with a chimeric flavivirus ( Kurosu et al, 2020 , 2023a ). Zellweger et al (2010) also developed a model using the DENV-2S221 strain in A129 mice.…”

Section: Introductionmentioning

confidence: 99%

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

Kurosu,

Sakai,

Ami

et al. 2024

Front. Microbiol.

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IntroductionSevere dengue is thought to be caused by an excessive host immune response.MethodsTo 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.ResultsAlthough 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.DiscussionThese 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.

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Section: Resultsmentioning

confidence: 99%