Residue 82 of the chikungunya virus E2 attachment protein modulates viral dissemination and arthritis in mice

Alison W. Ashbrook, Kristina A Burrack, Laurie A. Silva, Stephanie A. Montgomery, Mark T. Heise, Thomas E. Morrison, Terence S. Dermody

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has reemerged to cause profound epidemics of fever, rash, and arthralgia throughout sub-Saharan Africa, Southeast Asia, and the Caribbean. Like other arthritogenic alphaviruses, mechanisms of CHIKV pathogenesis are not well defined. Using the attenuated CHIKV strain 181/25 and virulent strain AF15561, we identified a residue in the E2 viral attachment protein that is a critical determinant of viral replication in cultured cells and pathogenesis in vivo. Viruses containing an arginine at E2 residue 82 displayed enhanced infectivity in mammalian cells but reduced infectivity in mosquito cells and 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 and serum at early times postinfection. Using wild-type and glycosaminoglycan (GAG)-deficient Chinese hamster ovary (CHO) cell lines and 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, and activation of inflammatory responses early in infection. Collectively, these results suggest a function for GAG utilization in regulating CHIKV tropism and host responses that contribute to arthritis.

Original languageEnglish (US)
Pages (from-to)12180-12192
Number of pages13
JournalJournal of virology
Volume88
Issue number21
DOIs
StatePublished - Jan 1 2014

Fingerprint

Chikungunya virus
Virus Attachment
Infectious Arthritis
viral proteins
arthritis
mice
Alphavirus
arginine
Arginine
Proteins
glycosaminoglycans
Viruses
Glycosaminoglycans
Culicidae
viruses
pathogenicity
pathogenesis
Viral Tropism
Southeastern Asia
tropisms

Cite this

Ashbrook, A. W., Burrack, K. A., Silva, L. A., Montgomery, S. A., Heise, M. T., Morrison, T. E., & Dermody, T. S. (2014). Residue 82 of the chikungunya virus E2 attachment protein modulates viral dissemination and arthritis in mice. Journal of virology, 88(21), 12180-12192. https://doi.org/10.1128/JVI.01672-14

Residue 82 of the chikungunya virus E2 attachment protein modulates viral dissemination and arthritis in mice. / Ashbrook, Alison W.; Burrack, Kristina A; Silva, Laurie A.; Montgomery, Stephanie A.; Heise, Mark T.; Morrison, Thomas E.; Dermody, Terence S.

In: Journal of virology, Vol. 88, No. 21, 01.01.2014, p. 12180-12192.

Research output: Contribution to journalArticle

Ashbrook, AW, Burrack, KA, Silva, LA, Montgomery, SA, Heise, MT, Morrison, TE & Dermody, TS 2014, 'Residue 82 of the chikungunya virus E2 attachment protein modulates viral dissemination and arthritis in mice', Journal of virology, vol. 88, no. 21, pp. 12180-12192. https://doi.org/10.1128/JVI.01672-14
Ashbrook AW, Burrack KA, Silva LA, Montgomery SA, Heise MT, Morrison TE et al. Residue 82 of the chikungunya virus E2 attachment protein modulates viral dissemination and arthritis in mice. Journal of virology. 2014 Jan 1;88(21):12180-12192. https://doi.org/10.1128/JVI.01672-14
Ashbrook, Alison W. ; Burrack, Kristina A ; Silva, Laurie A. ; Montgomery, Stephanie A. ; Heise, Mark T. ; Morrison, Thomas E. ; Dermody, Terence S. / Residue 82 of the chikungunya virus E2 attachment protein modulates viral dissemination and arthritis in mice. In: Journal of virology. 2014 ; Vol. 88, No. 21. pp. 12180-12192.
@article{8171fcac215b47e3bda5ceede5bd48ae,
title = "Residue 82 of the chikungunya virus E2 attachment protein modulates viral dissemination and arthritis in mice",
abstract = "Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has reemerged to cause profound epidemics of fever, rash, and arthralgia throughout sub-Saharan Africa, Southeast Asia, and the Caribbean. Like other arthritogenic alphaviruses, mechanisms of CHIKV pathogenesis are not well defined. Using the attenuated CHIKV strain 181/25 and virulent strain AF15561, we identified a residue in the E2 viral attachment protein that is a critical determinant of viral replication in cultured cells and pathogenesis in vivo. Viruses containing an arginine at E2 residue 82 displayed enhanced infectivity in mammalian cells but reduced infectivity in mosquito cells and 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 and serum at early times postinfection. Using wild-type and glycosaminoglycan (GAG)-deficient Chinese hamster ovary (CHO) cell lines and 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, and activation of inflammatory responses early in infection. Collectively, these results suggest a function for GAG utilization in regulating CHIKV tropism and host responses that contribute to arthritis.",
author = "Ashbrook, {Alison W.} and Burrack, {Kristina A} and Silva, {Laurie A.} and Montgomery, {Stephanie A.} and Heise, {Mark T.} and Morrison, {Thomas E.} and Dermody, {Terence S.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1128/JVI.01672-14",
language = "English (US)",
volume = "88",
pages = "12180--12192",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "21",

}

TY - JOUR

T1 - Residue 82 of the chikungunya virus E2 attachment protein modulates viral dissemination and arthritis in mice

AU - Ashbrook, Alison W.

AU - Burrack, Kristina A

AU - Silva, Laurie A.

AU - Montgomery, Stephanie A.

AU - Heise, Mark T.

AU - Morrison, Thomas E.

AU - Dermody, Terence S.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has reemerged to cause profound epidemics of fever, rash, and arthralgia throughout sub-Saharan Africa, Southeast Asia, and the Caribbean. Like other arthritogenic alphaviruses, mechanisms of CHIKV pathogenesis are not well defined. Using the attenuated CHIKV strain 181/25 and virulent strain AF15561, we identified a residue in the E2 viral attachment protein that is a critical determinant of viral replication in cultured cells and pathogenesis in vivo. Viruses containing an arginine at E2 residue 82 displayed enhanced infectivity in mammalian cells but reduced infectivity in mosquito cells and 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 and serum at early times postinfection. Using wild-type and glycosaminoglycan (GAG)-deficient Chinese hamster ovary (CHO) cell lines and 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, and activation of inflammatory responses early in infection. Collectively, these results suggest a function for GAG utilization in regulating CHIKV tropism and host responses that contribute to arthritis.

AB - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has reemerged to cause profound epidemics of fever, rash, and arthralgia throughout sub-Saharan Africa, Southeast Asia, and the Caribbean. Like other arthritogenic alphaviruses, mechanisms of CHIKV pathogenesis are not well defined. Using the attenuated CHIKV strain 181/25 and virulent strain AF15561, we identified a residue in the E2 viral attachment protein that is a critical determinant of viral replication in cultured cells and pathogenesis in vivo. Viruses containing an arginine at E2 residue 82 displayed enhanced infectivity in mammalian cells but reduced infectivity in mosquito cells and 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 and serum at early times postinfection. Using wild-type and glycosaminoglycan (GAG)-deficient Chinese hamster ovary (CHO) cell lines and 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, and activation of inflammatory responses early in infection. Collectively, these results suggest a function for GAG utilization in regulating CHIKV tropism and host responses that contribute to arthritis.

UR - http://www.scopus.com/inward/record.url?scp=84907965342&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907965342&partnerID=8YFLogxK

U2 - 10.1128/JVI.01672-14

DO - 10.1128/JVI.01672-14

M3 - Article

AN - SCOPUS:84907965342

VL - 88

SP - 12180

EP - 12192

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 21

ER -