title: Early restriction of alphavirus replication and dissemination contributes to age-dependent attenuation of systemic hyperinflammatory disease.
abstract: Severity of alphavirus infection in humans tends to be strongly age-dependent and several studies using laboratory-adapted Sindbis virus (SB) AR339 strains have indicated that SB-induced disease in mice is similarly contingent upon host developmental status. In the current studies, the consensus wild-type SB, TR339, and in vivo imaging technology have been utilized to examine virus replication and disease manifestations in mice infected subcutaneously at 5 days of age (5D) vs 11D. Initial virulence studies with TR339 indicated that this age range is coincident with rapid transition from fatal to non-fatal outcome. Fatal infection of 5D mice is characterized by high-titre serum viraemia, extensive virus replication in skin, fibroblast connective tissue, muscle and brain, and hyperinflammatory cytokine induction. In contrast, 11D-infected mice experience more limited virus replication and tissue damage and develop mild, immune-mediated pathologies including encephalitis. These results further establish the linkage between hyperinflammatory cytokine induction and fatal outcome of infection. In vivo imaging using luciferase-expressing viruses and non-propagative replicons revealed that host development results in a restriction of virus replication within individual infected cells that is manifested as a delay in reduction of virus replication in the younger mice. Thus, an important contributing factor in age-dependent resistance to alphavirus infection is restriction of replication within first infected cells in peripheral tissues, which may augment other developmentally regulated attenuating effects, such as increasing neuronal resistance to virus infection and apoptotic death.
authors.affiliation: Department of Microbiology and Immunology and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
authors.forename: Kate D
authors.initials: KD
authors.lastname: Ryman
authors.affiliation: Department of Microbiology and Immunology and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Gardner
authors.affiliation: Department of Microbiology and Immunology and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Meier
authors.affiliation: Department of Molecular Microbiology, Brown University, Providence, RI 02912, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Biron
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7290, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Johnston
authors.affiliation: Department of Microbiology and Immunology and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Klimstra
mesh_terms: D000375:Aging / Q000276:immunology*; D018354:Alphavirus Infections / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology / Q000821:virology; D000818:Animals; D000833:Animals, Suckling; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology; D051379:Mice; D012720:Severity of Illness Index; D012845:Sindbis Virus / Q000472:pathogenicity* / Q000502:physiology; D014766:Viremia / Q000276:immunology / Q000401:mortality / Q000503:physiopathology / Q000821:virology; D014774:Virulence; D014779:Virus Replication
chemical_list: D016207:Cytokines