Pathological Studies on Hantaan Virus-Infected Mice Simulating Severe Hemorrhagic Fever with Renal Syndrome

Zhouoxing Wei; Kenta Shimizu; Rakiiya S Sarii; Devinda S Muthusinghe; Sithumini M W Lokupathirage; Junko Nio-Kobayashi; Kumiko Yoshimatsu

doi:10.3390/v14102247

Pathological Studies on Hantaan Virus-Infected Mice Simulating Severe Hemorrhagic Fever with Renal Syndrome

Viruses. 2022 Oct 13;14(10):2247. doi: 10.3390/v14102247.

Authors

Zhouoxing Wei^{1

2}, Kenta Shimizu³, Rakiiya S Sarii^{1

2}, Devinda S Muthusinghe^{2

4}, Sithumini M W Lokupathirage^{1

2}, Junko Nio-Kobayashi⁵, Kumiko Yoshimatsu^{1

2}

Affiliations

¹ Graduate School of Infectious Diseases, Hokkaido University, Sapporo 060-0815, Japan.
² Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
³ Department of Infectious Diseases and Host Defense, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan.
⁴ WISE Program for One Health Frontier Graduate School of Excellence, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
⁵ Laboratory of Histology and Cytology, Department of Anatomy, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.

Abstract

Hantaan virus is the causative agent of hemorrhagic fever with renal syndrome (HFRS). The Hantaan virus strain, Korean hemorrhagic fever virus clone-5 (KHF5), causes weight loss and renal hemorrhage in laboratory mice. Clone-4 (KHF4), which has a single E417K amino acid change in its glycoprotein, is an avirulent variant. In this study, KHF4 and KHF5 were compared to evaluate pathological differences in mice in vitro and in vivo. The characteristics of the two glycoproteins were not significantly different in vitro. However, the virulent KHF5 strain targeted the lungs and caused pneumonia and edema in vivo. Both strains induced high infectivity levels in the liver and caused hepatitis; however, petechial hemorrhage and glycogen storage reduction were observed in KHF5-infected mice alone. Renal hemorrhage was observed using viral antigens in the tubular region of KHF5-infected mice. In addition, an increase in white blood cell levels and neutrophilia were found in KHF5-infected mice. Microarray analysis of liver cells showed that CD8+ T cell activation, acute-phase protein production, and neutrophil activation was induced by KHF5 infection. KHF5 infectivity was significantly increased in vivo and the histological and clinicopathological findings were similar to those in patients with HFRS.

Keywords: Hantaan virus; mouse model; neutrophil activation; renal function; virulence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute-Phase Proteins
Amino Acids
Animals
Antigens, Viral / analysis
Glycogen
Hantaan virus*
Hemorrhage
Hemorrhagic Fever with Renal Syndrome*
Mice

Substances

Antigens, Viral
Acute-Phase Proteins
Glycogen
Amino Acids

Grants and funding

This research was funded by The Japanese Society for the Promotion of Science (JSPS) KAKENHI (19K10595, 16K08801, 20K07510); Science and Technology Research Partnership for Sustainable Development (SATREPS; JP22jm0110019).