title: The Ectodomain of Glycoprotein from the Candid#1 Vaccine Strain of Junin Virus Rendered Machupo Virus Partially Attenuated in Mice Lacking IFN-αβ/γ Receptor.
abstract: Machupo virus (MACV), a New World arenavirus, is the etiological agent of Bolivian hemorrhagic fever (BHF). Junin virus (JUNV), a close relative, causes Argentine hemorrhagic fever (AHF). Previously, we reported that a recombinant, chimeric MACV (rMACV/Cd#1-GPC) expressing glycoprotein from the Candid#1 (Cd#1) vaccine strain of JUNV is completely attenuated in a murine model and protects animals from lethal challenge with MACV. A rMACV with a single F438I substitution in the transmembrane domain (TMD) of GPC, which is equivalent to the F427I attenuating mutation in Cd#1 GPC, was attenuated in a murine model but genetically unstable. In addition, the TMD mutation alone was not sufficient to fully attenuate JUNV, indicating that other domains of the GPC may also contribute to the attenuation. To investigate the requirement of different domains of Cd#1 GPC for successful attenuation of MACV, we rescued several rMACVs expressing the ectodomain of GPC from Cd#1 either alone (MCg1), along with the TMD F438I substitution (MCg2), or with the TMD of Cd#1 (MCg3). All rMACVs exhibited similar growth curves in cultured cells. In mice, the MCg1 displayed significant reduction in lethality as compared with rMACV. The MCg1 was detected in brains and spleens of MCg1-infected mice and the infection was associated with tissue inflammation. On the other hand, all animals survived MCg2 and MCg3 infection without detectable levels of virus in various organs while producing neutralizing antibody against Cd#1. Overall our data suggest the indispensable role of each GPC domain in the full attenuation and immunogenicity of rMACV/Cd#1 GPC.
authors: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors: Takaaki
authors: T
authors: Koma
authors: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors: Cheng
authors: C
authors: Huang
authors: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors: Judith F
authors: JF
authors: Aronson
authors: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors: Aida G
authors: AG
authors: Walker
authors: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors: Milagros
authors: M
authors: Miller
authors: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors: Jeanon N
authors: JN
authors: Smith
authors: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors: Michael
authors: M
authors: Patterson
authors: Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors: Slobodan
authors: S
authors: Paessler
mesh_terms: D000072283:A549 Cells; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D006224:Cricetinae; D004195:Disease Models, Animal; D000882:Haplorhini; D006478:Hemorrhagic Fever, American / Q000517:prevention & control; D018051:Junin virus / Q000276:immunology* / Q000472:pathogenicity; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009500:Neutralization Tests; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics; D011994:Recombinant Proteins / Q000276:immunology; D014613:Vaccines, Attenuated / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C555941:GPC protein, junin virus; D008562:Membrane Glycoproteins; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D014613:Vaccines, Attenuated; D014759:Viral Envelope Proteins; D014765:Viral Vaccines