Pathogenesis Of Emerging Severe Fever With Thrombocytopenia ...

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Abstract

The discovery of an emerging viral disease, severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), has prompted the need to understand pathogenesis of SFTSV. We are unique in establishing an infectious model of SFTS in C57/BL6 mice, resulting in hallmark symptoms of thrombocytopenia and leukocytopenia. Viral RNA and histopathological changes were identified in the spleen, liver, and kidney. However, viral replication was only found in the spleen, which suggested the spleen to be the principle target organ of SFTSV. Moreover, the number of macrophages and platelets were largely increased in the spleen, and SFTSV colocalized with platelets in cytoplasm of macrophages in the red pulp of the spleen. In vitro cellular assays further revealed that SFTSV adhered to mouse platelets and facilitated the phagocytosis of platelets by mouse primary macrophages, which in combination with in vivo findings, suggests that SFTSV-induced thrombocytopenia is caused by clearance of circulating virus-bound platelets by splenic macrophages. Thus, this study has elucidated the pathogenic mechanisms of thrombocytopenia in a mouse model resembling human SFTS disease.

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The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Dynamic profile of pathological changes…

Fig. 1.

Dynamic profile of pathological changes in mice infected with SFTSV. Representative H&E-stained tissue…

Fig. 1. Dynamic profile of pathological changes in mice infected with SFTSV. Representative H&E-stained tissue sections from SFTSV-infected mice and mock mice are shown. Areas of interest (AOI) are enlarged, and quantitative graphs are presented at the right. (A) Decreased cellularity in the red pulp (RP) of the spleen at day 1 p.i.; no obvious changes are visualized in the white pulp (WP). (B) Increased megakaryocytes in the spleen at day 3 p.i.. Arrowheads indicate megakaryocytes. (C) Increased megakaryocytes in the bone marrow at day 3 p.i. Arrowheads indicate megakaryocytes. (D) In liver at day 14 p.i., arrowheads show hepatocyte necrosis with shrinking nucleic or hepatocyte degradation with balloon-like empty cytoplasm. (E) In the kidney at day 14 p.i., arrowheads show impaired renal capsules. In A and B, the images and AOI are 100× and 200×, respectively. In C–E, the images and AOI are 200× and 400×, respectively. In quantitative graphs, red dots and blue dots indicate SFTSV-infected mice and mock mice, respectively, and lines indicate the means. *P < 0.05.
Fig. 2.

Fig. 2.

Identification and colocalization of SFTSV,…

Fig. 2.

Identification and colocalization of SFTSV, macrophages, and platelets in SFTSV-infected spleen. ( A …

Fig. 2. Identification and colocalization of SFTSV, macrophages, and platelets in SFTSV-infected spleen. (A) SFTSV, macrophages, and platelets were identified by immuno-histochemistry in the spleen of Mock mice or SFTSV-infected mice at day 3. Representative images and enlarged AOI are taken at an original magnification of 200× and 400×, respectively. (B) Confocal microscopy to examine colocalization of SFTSV (in green), macrophages (in red), and platelets (in blue) in the SFTSV-infected spleen collected on day 3 p.i. The representative fluorescent images and embedded AOI were originally taken at 200× and 400×, respectively.
Fig. 3.

Fig. 3.

Phagocytosis of SFTSV-bound platelets by…

Fig. 3.

Phagocytosis of SFTSV-bound platelets by macrophages. ( A ) The confocal image shows…

Fig. 3. Phagocytosis of SFTSV-bound platelets by macrophages. (A) The confocal image shows viral N protein (in green) in mouse primary macrophages (in blue). The graph shows dynamic virus replication in mouse primary macrophages and the virus released into culturing supernatants. (B) Real-time PCR quantification detected a gradient of adherence of SFTSV on mouse platelets corresponding to the amount of virus added into platelets. The graph on the right shows the virus amount detected in cultured virus-adhered platelets as well as in culturing supernatants at the indicated time points. (C) Confocal images show mouse primary macrophages cocultured with normal platelets (Top), mouse primary macrophages cocultured with platelets with adherent SFTSV (Middle), mouse macrophages previously infected by SFTSV for 3 d before coculturing with normal platelets (Bottom). All images were taken at an original magnification of 400×. Quantification of macrophage phagocytosis of fluorescent platelets is shown in Fig. S2D.
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References

    1. Yu XJ, et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med. 2011;364:1523–1532. - PMC - PubMed
    1. Pifat DY, Smith JF. Punta Toro virus infection of C57BL/6J mice: A model for phlebovirus-induced disease. Microb Pathog. 1987;3:409–422. - PubMed
    1. Cusi MG, et al. Development of a mouse model for the study of Toscana virus pathogenesis. Virology. 2005;333:66–73. - PubMed
    1. Fisher AF, et al. Induction of severe disease in hamsters by two sandfly fever group viruses, Punta toro and Gabek Forest (Phlebovirus, Bunyaviridae), similar to that caused by Rift Valley fever virus. Am J Trop Med Hyg. 2003;69:269–276. - PubMed
    1. Molyneux G, et al. The haemotoxicity of mitomycin in a repeat dose study in the female CD-1 mouse. Int J Exp Pathol. 2005;86:415–430. - PMC - PubMed
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