Interferon-alpha/beta deficiency greatly exacerbates arthritogenic disease in mice infected with wild-type chikungunya virus but not with the cell culture-adapted live-attenuated 181/25 vaccine candidate.
In humans, chikungunya virus (CHIKV) infection causes fever, rash, and acute and persisting polyarthralgia/arthritis associated with joint swelling. We report a new CHIKV disease model in adult mice that distinguishes the wild-type CHIKV-LR strain from the live-attenuated vaccine strain (CHIKV-181/25). Although eight-week old normal mice inoculated in the hind footpad developed no hind limb swelling with either virus, CHIKV-LR replicated in musculoskeletal tissues and caused detectable inflammation. In mice deficient in STAT1-dependent interferon (IFN) responses, CHIKV-LR caused significant swelling of the inoculated and contralateral limbs and dramatic inflammatory lesions, while CHIKV-181/25 vaccine and another arthritogenic alphavirus, Sindbis, failed to induce swelling. IFN responses suppressed CHIKV-LR and CHIKV-181/25 replication equally in dendritic cells in vitro whereas macrophages were refractory to infection independently of STAT1-mediated IFN responses. Glycosaminoglycan (GAG) binding may be a CHIKV vaccine attenuation mechanism as CHIKV-LR infectivity was not dependent upon GAG, while CHIKV-181/25 was highly dependent.
Center for Vaccine Research and Dept. of Microbiology & Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
Christina L
CL
Gardner
Crystal W
CW
Burke
Stephen T
ST
Higgs
William B
WB
Klimstra
Kate D
KD
Ryman
D018354:Alphavirus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D000818:Animals; D001170:Arthritis, Infectious / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D065632:Chikungunya Fever; D002646:Chikungunya virus / Q000276:immunology* / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology*; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014613:Vaccines, Attenuated / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*; D014779:Virus Replication
D016898:Interferon-alpha; D014613:Vaccines, Attenuated; D014765:Viral Vaccines; D016899:Interferon-beta