Autor(es): Ashbrook Alison W, Burrack Kristina S, Silva Laurie A, Montgomery Stephanie A, Heise Mark T, Morrison Thomas E, Dermody Terence S

Resumo: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has reemerged to cause profound epidemics of fever, rash, - arthralgia throughout sub-Saharan Africa, Southeast Asia, - the Caribbean. Like other arthritogenic alphaviruses, mechanisms of CHIKV pathogenesis are not well defined. Using the attenuated CHIKV strain 181/25 - virulent strain AF15561, we identified a residue in the E2 viral attachment protein that is a critical determinant of viral replication in cultured cells - pathogenesis in vivo. Viruses containing an arginine at E2 residue 82 displayed enhanced infectivity in mammalian cells but reduced infectivity in mosquito cells - diminished virulence in a mouse model of CHIKV disease. Mice inoculated with virus containing an arginine at this position exhibited reduced swelling at the site of inoculation with a concomitant decrease in the severity of necrosis in joint-associated tissues. Viruses containing a glycine at E2 residue 82 produced higher titers in the spleen - serum at early times postinfection. Using wild-type - glycosaminoglycan (GAG)-deficient Chinese hamster ovary (CHO) cell lines - soluble GAGs, we found that an arginine at residue 82 conferred greater dependence on GAGs for infection of mammalian cells. These data suggest that CHIKV E2 interactions with GAGs diminish dissemination to lymphoid tissue, establishment of viremia, - activation of inflammatory responses early in infection. Collectively, these results suggest a function for GAG utilization in regulating CHIKV tropism - host responses that contribute to arthritis. CHIKV is a reemerging alphavirus of global significance with high potential to spread into new, immunologically naive populations. The severity of CHIKV disease, particularly its propensity for chronic musculoskeletal manifestations, emphasizes the need for identification of genetic determinants that dictate CHIKV virulence in the host. To better underst- mechanisms of CHIKV pathogenesis, we probed the function of an amino acid polymorphism in the E2 viral attachment protein using a mouse model of CHIKV musculoskeletal disease. In addition to influencing glycosaminoglycan utilization, we identified roles for this polymorphism in differential infection of mammalian - mosquito cells - targeting of CHIKV to specific tissues within infected mice. These studies demonstrate a correlation between CHIKV tissue tropism - virus-induced pathology modulated by a single polymorphism in E2, which in turn illuminates potential targets for vaccine - antiviral drug development.

Imprenta: Journal of Virology, v. 88, n. 21, p. 12180-12192, 2014

Identificador do objeto digital: 10.1128/JVI.01672-14

Descritores: Chikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - Cytopathology ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Proteins ; Chikungunya Virus - Virus ; Chikungunya virus - Vaccine ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Epidemic ; Chikungunya virus - Immunology

Data de publicação: 2014

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