- 作者: Huixin Chen, Patchara Phuektes, Li Sze Yeo, Yi Hao Wong, Regina Ching Hua Lee, Bowen Yi, Xinjun Hou, Sen Liu, Yu Cai & Justin Jang Hann Chu
- 作者服務機構: 1.Collaborative and Translation Unit for HFMD, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 2.Department of Biological Sciences, National University of Singapore, Singapore, Singapore 3.Division of Pathobiology, Faculty of Veterinary Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand 4.Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 5.Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 6.School of Applied Science, Republic Polytechnic, Singapore, Singapore 7.Temasek Life Sciences Laboratory, National University of Singapore, Singapore, Singapore
- 中文摘要:
- 英文摘要:
Background
Chikungunya virus (CHIKV) has reemerged as a major public health concern, causing chikungunya fever with increasing cases and neurological complications.
Methods
In the present study, we investigated a low-passage human isolate of the East/ Central/South African (ECSA) lineage of CHIKV strain LK(EH)CH6708, which exhibited a mix of small and large viral plaques. The small and large plaque variants were isolated and designated as CHIKV-SP and CHIKV-BP, respectively. CHIKV-SP and CHIKV-BP were characterized in vitro and in vivo to compare their virus production and virulence. Additionally, whole viral genome analysis and reverse genetics were employed to identify genomic virulence factors.
Results
CHIKV-SP demonstrated lower virus production in mammalian cells and attenuated virulence in a murine model. On the other hand, CHIKV-BP induced higher pro-inflammatory cytokine levels, compromised the integrity of the blood–brain barrier, and led to astrocyte infection in mouse brains. Furthermore, the CHIKV-SP variant had limited transmission potential in Aedes albopictus mosquitoes, likely due to restricted dissemination. Whole viral genome analysis revealed multiple genetic mutations in the CHIKV-SP variant, including a Glycine (G) to Arginine (R) mutation at position 55 in the viral E2 glycoprotein. Reverse genetics experiments confirmed that the E2-G55R mutation alone was sufficient to reduce virus production in vitro and virulence in mice.
Conclusions
These findings highlight the attenuating effects of the E2-G55R mutation on CHIKV pathogenicity and neurovirulence and emphasize the importance of monitoring this mutation in natural infections. - 中文關鍵字:
- 英文關鍵字: Chikungunya virus, Plaque size, Neurovirulence, Pathogenesis, Attenuation