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

• Published in: Frontiers in microbiology Vol. 15; p. 1367672
• Main Authors: Kurosu, Takeshi, Sakai, Yusuke, Ami, Yasusi, Shimojima, Masayuki, Yoshikawa, Tomoki, Fukushi, Shuetsu, Nagata, Noriyo, Suzuki, Tadaki, Ebihara, Hideki, Saijo, Masayuki
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 14.03.2024
• Subjects: bone marrow suppression; cytokine storm; Microbiology; myeloid cells; pathogenic mechanisms; severe dengue; vascular leakage; vascular leakage; pathogenic mechanisms; cytokine storm; myeloid cells; severe dengue; bone marrow suppression; viral adaptation
• ISSN: 1664-302X; 1664-302X
• DOI: 10.3389/fmicb.2024.1367672

Severe dengue is thought to be caused by an excessive host immune response. To study the pathogenesis of severe dengue, we developed a novel model using LysM Cre mice carrying depleted expression only in subsets of murine myeloid cells. Although dengue virus (DENV) clinical isolates were not virulent in LysM Cre 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. 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.