Tupaia belangeri better reflects the typical symptoms of Chikungunya virus infection than mice: a comparative study

Chikungunya virus (CHIKV) infection in humans is typically characterized by acute febrile illness, rash, and polyarthralgia, and often progresses to chronic arthralgia. However, existing small-animal models fail to capture both the acute and chronic phases of the disease. In this study, we compared Chinese tree shrews ( Tupaia belangeri ) and C57BL/6 mice in terms of infection dynamics, viral characteristics, histopathological changes, and immune responses. Following dual-site inoculation (subcutaneous injection into the abdomen and footpad), Tupaia belangeri exhibited typical symptoms that more closely resembled those of humans, including pronounced fever, foot swelling, and skin lesions, and were accompanied by higher and more sustained viral loads in blood and multiple tissues. Histopathological examination revealed marked inflammation and tissue damage in muscle and joint tissues, consistent with pathological changes observed in humans. Transcriptomic analysis further demonstrated significant upregulation of multiple key immune-related genes ( CXCL10, ISG15, IFIT3, SERPING1, MCEMP1, IFI6 ), indicating a human-like immune response profile. Collectively, our results show that Tupaia belangeri faithfully mirrors the infection features, viral dynamics, and immune responses of human CHIKV infection, establishing it as a valuable model for dissecting disease mechanisms and testing vaccines or antiviral therapies. • Tupaia belangeri better recapitulates typical CHIKV symptoms than mice, including fever, rash, and foot swelling. • Tupaia belangeri develops higher and more persistent viremia with pronounced joint inflammation and strong ISG activation. • Our findings support Tupaia belangeri as a practical and potentially valuable model for CHIKV pathogenesis and therapeutic research.