Macrophage scavenger receptor 1 controls Chikungunya virus infection through autophagy in mice
Authors: Yang, Long; Geng, Tingting; Yang, Guang; Ma, Jinzhu; Wang, Leilei; Ketkar, Harshada; Yang, Duomeng; Lin, Tao; Hwang, Jesse; Zhu, Shu; Wang, Yanlin; Dai, Jianfeng; You, Fuping; Cheng, Gong; Vella, Anthony T.; Flavell, Richard. A.; Fikrig, Erol; Wang, Penghua
UsingMsr1knockout mice, Long Yang et al. demonstrate that macrophage scavenger receptor 1 (MSR1) activates autophagy to restrict the proliferation of Chikungunya virus, an alphavirus that causes crippling joint stiffness. This study provides insights into how host cellular machinery fights off Chikungunya virus. Macrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density lipoproteins and plays an important antiviral role. However, the molecular mechanism underlying MSR1 antiviral actions remains elusive. We report that MSR1 activates autophagy to restrict infection of Chikungunya virus (CHIKV), an arthritogenic alphavirus that causes acute and chronic crippling arthralgia. Msr1 expression was rapidly upregulated after CHIKV infection in mice.Msr1knockout mice had elevated viral loads and increased susceptibility to CHIKV arthritis along with a normal type I IFN response. Induction of LC3 lipidation by CHIKV, a marker of autophagy, was reduced inMsr1(-/-)cells. Mechanistically, MSR1 interacted with ATG12 through its cytoplasmic tail and this interaction was enhanced by CHIKV nsP1 protein. MSR1 repressed CHIKV replication through ATG5-ATG12-ATG16L1 and this was dependent on the FIP200-and-WIPI2-binding domain, but not the WD40 domain of ATG16L1. Our results elucidate an antiviral role for MSR1 involving the autophagic function of ATG5-ATG12-ATG16L1.
The vaccinia virus based Sementis Copenhagen Vector vaccine against Zika and chikungunya is immunogenic in non-human primates
Authors: Prow, Natalie A.; Liu, Liang; McCarthy, Mary K.; Walters, Kevin; Kalkeri, Raj; Geiger, Jillian; Koide, Fusataka; Cooper, Tamara H.; Eldi, Preethi; Nakayama, Eri; Diener, Kerrilyn R.; Howley, Paul M.; Hayball, John D.; Morrison, Thomas E.; Suhrbier, Andreas
The Sementis Copenhagen Vector (SCV) is a new vaccinia virus-derived, multiplication-defective, vaccine technology assessed herein in non-human primates. Indian rhesus macaques (Macaca mulatta) were vaccinated with a multi-pathogen recombinant SCV vaccine encoding the structural polyproteins of both Zika virus (ZIKV) and chikungunya virus (CHIKV). After one vaccination, neutralising antibody responses to ZIKV and four strains of CHIKV, representative of distinct viral genotypes, were generated. A second vaccination resulted in significant boosting of neutralising antibody responses to ZIKV and CHIKV. Following challenge with ZIKV, SCV-ZIKA/CHIK-vaccinated animals showed significant reductions in viremias compared with animals that had received a control SCV vaccine. Two SCV vaccinations also generated neutralising and IgG ELISA antibody responses to vaccinia virus. These results demonstrate effective induction of immunity in non-human primates by a recombinant SCV vaccine and illustrates the utility of SCV as a multi-disease vaccine platform capable of delivering multiple large immunogens.