Since the chikungunya virus (CHIKV) outbreaks in 2004, scientists around the world have been trying to understand how the pathogen causes its classical symptoms of fever and joint swelling which, in some cases, can last for years. The protein Viperin is known to exert a protective, antiviral effect by interfering with virus replication, although recent studies have suggested that Viperin may also regulate the host immune response during infection.

In this study, researchers led by Lisa F.P. Ng at the Singapore Immunology Network (SIgN)demonstrated that the loss of Viperin in mice is responsible for a host-damaging immune response to CHIKV infection. The team first showed that CHIKV-infected mice lacking the Viperin gene (Viperin-KO mice) had greater joint swelling than normal mice. Joint swelling was alleviated when the researchers used an antibody to deplete a subset of immune cells—CD4+ T-cells—in Viperin-KO infected mice, showing that CD4+ T-cells were responsible for more severe joint swelling during infection.

Yet, the researchers noted that the number of CD4+ T-cells and the viral burden in the joints of Viperin-KO and normal mice were almost equal. This led them to investigate the functions of the infiltrating immune cell populations. “We showed that infiltrating monocytes and T-cells have an increased activated and pathogenic state during virus infection in Viperin-KO mice compared to normal mice,” Ng said. For example, the levels of pro-inflammatory molecules such as TNFα, IL-1α, IL-1β and IL-2 were higher in the joints of infected Viperin-KO mice than normal controls, which worsened joint swelling.

Ng’s team also transferred immune cells from Viperin-KO mice into normal mice that had been depleted of their native immune system, and vice versa. This allowed them to assess whether the loss of Viperin in non-immune cells contributed towards joint swelling. Their findings revealed that non-immune cells lacking Viperin also increase the extent of joint swelling during CHIKV infection.

“These results further highlight that Viperin’s role during infections is not merely antiviral—Viperin also influences the way our body’s immune system reacts to the infection and triggers pathology. Therefore, there is a need to better understand the cellular mechanisms of Viperin on the immune system,” Ng explained, adding that this is an area her lab plans to investigate more deeply in the future.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN).