title: Nipah Virus C and W Proteins Contribute to Respiratory Disease in Ferrets.
abstract: Nipah virus (NiV) is a highly lethal paramyxovirus that recently emerged as a causative agent of febrile encephalitis and severe respiratory disease in humans. The ferret model has emerged as the preferred small-animal model with which to study NiV disease, but much is still unknown about the viral determinants of NiV pathogenesis, including the contribution of the C protein in ferrets. Additionally, studies have yet to examine the synergistic effects of the various P gene products on pathogenesis in animal models. Using recombinant NiVs (rNiVs), we examine the sole contribution of the NiV C protein and the combined contributions of the C and W proteins in the ferret model of NiV pathogenesis. We show that an rNiV void of C expression resulted in 100% mortality, though with limited respiratory disease, like our previously reported rNiV void of W expression; this finding is in stark contrast to the attenuated phenotype observed in previous hamster studies utilizing rNiVs void of C expression. We also observed that an rNiV void of both C and W expression resulted in limited respiratory disease; however, there was severe neurological disease leading to 60% mortality, and the surviving ferrets demonstrated sequelae similar to those for human survivors of NiV encephalitis.
  
  
  
  Nipah virus (NiV) is a human pathogen capable of causing lethal respiratory and neurological disease. Many human survivors have long-lasting neurological impairment. Using a ferret model, this study demonstrated the roles of the NiV C and W proteins in pathogenesis, where lack of either the C or the W protein independently decreased the severity of clinical respiratory disease but did not decrease lethality. Abolishing both C and W expression, however, dramatically decreased the severity of respiratory disease and the level of destruction of splenic germinal centers. These ferrets still suffered severe neurological disease: 60% succumbed to disease, and the survivors experienced long-term neurological impairment, such as that seen in human survivors. This new ferret NiV C and W knockout model may allow, for the first time, the examination of interventions to prevent or mitigate the neurological damage and sequelae experienced by human survivors.
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Satterfield
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Cross
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Karla A
authors.initials: KA
authors.lastname: Fenton
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Borisevich
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Krystle N
authors.initials: KN
authors.lastname: Agans
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Deer
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Graber
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Basler
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA twgeisbe@utmb.edu.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Geisbert
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Mire
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005289:Ferrets; D045464:Henipavirus Infections / Q000150:complications* / Q000276:immunology / Q000821:virology; D006801:Humans; D045405:Nipah Virus / Q000472:pathogenicity*; D010750:Phosphoproteins / Q000276:immunology*; D012140:Respiratory Tract Diseases / Q000209:etiology* / Q000473:pathology; D014709:Vero Cells; D019562:Viral Load; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; C543302:C protein, Nipah virus; D010750:Phosphoproteins; D014764:Viral Proteins; C501252:W protein, Nipah virus