title: Multiple immune factors are involved in controlling acute and chronic chikungunya virus infection.
abstract: The recent epidemic of the arthritogenic alphavirus, chikungunya virus (CHIKV) has prompted a quest to understand the correlates of protection against virus and disease in order to inform development of new interventions. Herein we highlight the propensity of CHIKV infections to persist long term, both as persistent, steady-state, viraemias in multiple B cell deficient mouse strains, and as persistent RNA (including negative-strand RNA) in wild-type mice. The knockout mouse studies provided evidence for a role for T cells (but not NK cells) in viraemia suppression, and confirmed the role of T cells in arthritis promotion, with vaccine-induced T cells also shown to be arthritogenic in the absence of antibody responses. However, MHC class II-restricted T cells were not required for production of anti-viral IgG2c responses post CHIKV infection. The anti-viral cytokines, TNF and IFNγ, were persistently elevated in persistently infected B and T cell deficient mice, with adoptive transfer of anti-CHIKV antibodies unable to clear permanently the viraemia from these, or B cell deficient, mice. The NOD background increased viraemia and promoted arthritis, with B, T and NK deficient NOD mice showing high-levels of persistent viraemia and ultimately succumbing to encephalitic disease. In wild-type mice persistent CHIKV RNA and negative strand RNA (detected for up to 100 days post infection) was associated with persistence of cellular infiltrates, CHIKV antigen and stimulation of IFNα/β and T cell responses. These studies highlight that, secondary to antibodies, several factors are involved in virus control, and suggest that chronic arthritic disease is a consequence of persistent, replicating and transcriptionally active CHIKV RNA.
authors.affiliation: QIMR Berghofer Medical Research Institute, and the Australian Infectious Diseases Research Centre, Brisbane, Queensland, Australia; School of Medicine/School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Yee Suan
authors.initials: YS
authors.lastname: Poo
authors.affiliation: QIMR Berghofer Medical Research Institute, and the Australian Infectious Diseases Research Centre, Brisbane, Queensland, Australia; School of Medicine/School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Penny A
authors.initials: PA
authors.lastname: Rudd
authors.affiliation: QIMR Berghofer Medical Research Institute, and the Australian Infectious Diseases Research Centre, Brisbane, Queensland, Australia.
authors.forename: Joy
authors.initials: J
authors.lastname: Gardner
authors.affiliation: QIMR Berghofer Medical Research Institute, and the Australian Infectious Diseases Research Centre, Brisbane, Queensland, Australia; School of Medicine/School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Jane A C
authors.initials: JA
authors.lastname: Wilson
authors.affiliation: Institut National de Recherche Agronomique, Unité Mixte de Recherche 703, Oniris, Nantes, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Larcher
authors.affiliation: Institut National de Recherche Agronomique, Unité Mixte de Recherche 703, Oniris, Nantes, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Colle
authors.affiliation: QIMR Berghofer Medical Research Institute, and the Australian Infectious Diseases Research Centre, Brisbane, Queensland, Australia.
authors.forename: Thuy T
authors.initials: TT
authors.lastname: Le
authors.affiliation: School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Helder I
authors.initials: HI
authors.lastname: Nakaya
authors.affiliation: Public Health Virology Laboratory, Department of Health, Queensland Government, Brisbane, Queensland, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Warrilow
authors.affiliation: Lotterywest State Biomedical Facility Genomics, Royal Perth Hospital, Perth, Western Australia, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Allcock
authors.affiliation: School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
authors.forename: Helle
authors.initials: H
authors.lastname: Bielefeldt-Ohmann
authors.affiliation: QIMR Berghofer Medical Research Institute, and the Australian Infectious Diseases Research Centre, Brisbane, Queensland, Australia.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Schroder
authors.affiliation: School of Medicine/School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Khromykh
authors.affiliation: QIMR Berghofer Medical Research Institute, and the Australian Infectious Diseases Research Centre, Brisbane, Queensland, Australia; School of Natural Sciences, Griffith University, Nathan, Australia.
authors.forename: José A
authors.initials: JA
authors.lastname: Lopez
authors.affiliation: QIMR Berghofer Medical Research Institute, and the Australian Infectious Diseases Research Centre, Brisbane, Queensland, Australia; School of Medicine/School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Queensland, Australia; School of Natural Sciences, Griffith University, Nathan, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Suhrbier
mesh_terms: D000208:Acute Disease; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D065632:Chikungunya Fever / Q000235:genetics / Q000276:immunology* / Q000821:virology; D002646:Chikungunya virus / Q000276:immunology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D012367:RNA, Viral / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D012367:RNA, Viral