A Mouse-Adapted CHIKV Strain Harboring E2-K200R and Non-Structural Mutations Exhibits Enhanced Pathogenicity in
Cong Tang1, Bai Li1, Qing Huang1
1Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College (IMBCAMS&PUMC), 935 Jiaoling Road, Kunming 650118, China.
Abstract:
Chikungunya virus (CHIKV) pathogenesis research has long been constrained by the lack of suitable immunocompetent rodent models. Through serial passaging in A129 and C57BL/6 mice, we obtained an adapted strain (CHIKV-Adapt) harboring an E2-K200R substitution along with non-structural protein mutations. Phenotypic analysis in C57BL/6 mice, BALB/c mice, and hamster models demonstrated that compared to the wild-type virus CHIKV-Adapt induced significantly higher and more prolonged viremia, broader tissue tropism, and more severe internal joint inflammation, without exacerbating external swelling. Notably, the K200R mutation did not alter the viral replication kinetics in vitro and was predicted not to affect its binding pattern to the MXRA8 receptor. Furthermore, mice challenged 160 days after primary infection exhibited nearly complete protective immunity. These findings indicate that E2-K200R is a critical adaptive mutation that, together with accompanying non-structural mutations, significantly enhances CHIKV replication capacity and pathogenicity in immunocompetent rodents without changing its in vitro replication ability or predicted receptor-binding mode. The acquisition of this adapted strain provides a new tool for CHIKV pathogenesis research and vaccine evaluation.
Insights
Researchers developed an adapted Chikungunya virus (CHIKV) strain, CHIKV-Adapt, for immunocompetent rodent models. This new tool enhances CHIKV pathogenesis research and vaccine evaluation by improving viral replication and pathogenicity in these models.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Chikungunya virus (CHIKV) research is limited by the absence of effective immunocompetent rodent models.
- Developing such models is crucial for understanding CHIKV pathogenesis and evaluating vaccines.
Purpose of the Study:
- To create and characterize an adapted CHIKV strain (CHIKV-Adapt) suitable for immunocompetent rodent models.
- To assess the enhanced pathogenicity and replication of CHIKV-Adapt in vivo.
Main Methods:
- Serial passaging of CHIKV in A129 and C57BL/6 mice to adapt the virus.
- Phenotypic analysis of CHIKV-Adapt in C57BL/6 mice, BALB/c mice, and hamsters.
- In vitro viral replication assays and in silico receptor binding predictions.
Main Results:
- CHIKV-Adapt, featuring an E2-K200R substitution and non-structural mutations, showed higher and prolonged viremia in immunocompetent mice and hamsters.
- The adapted strain exhibited broader tissue tropism and more severe internal joint inflammation.
- The K200R mutation did not affect in vitro replication or predicted MXRA8 receptor binding.
Conclusions:
- The E2-K200R mutation is key to CHIKV adaptation in immunocompetent rodents, enhancing pathogenicity without altering in vitro characteristics.
- CHIKV-Adapt provides a valuable new model for studying Chikungunya virus pathogenesis and assessing vaccine efficacy.
