title: Induction of virus-specific effector immune cell response limits virus replication and severe disease in mice infected with non-lethal West Nile virus Eg101 strain.
abstract: BACKGROUND
  West Nile virus (WNV) is a neurotropic flavivirus that has emerged globally as a significant cause of viral encephalitis in humans. Herein, we investigated the immunological responses induced by two phylogenetically related WNV strains of lineage 1, WNV NY99, and WNV Eg101.
  
  
  METHODS
  Eight-week-old C57BL/6J mice were inoculated with WNV NY99 or WNV Eg101 and mortality, virus burden in the periphery and brain, type 1 interferon response, WNV-specific antibodies, leukocyte infiltration, and inflammatory responses were analyzed.
  
  
  RESULTS
  As expected, WNV NY99 infected mice demonstrated high morbidity and mortality, whereas no morbidity and mortality was observed in WNV Eg101 infected mice. Virus titers were comparable in the serum of both WNV NY99 and WNV Eg101 infected mice at day 3 after inoculation; however, at day 6, the virus was cleared from WNV Eg101 infected mice but the virus titer remained high in the WNV NY99 infected mice. Virus was detected in the brains of both WNV NY99 and Eg101 infected mice, albeit significantly higher in the brains of WNV NY99 infected mice. Surprisingly, levels of type 1 interferon and WNV-specific antibodies were significantly higher in the serum and brains of WNV NY99 infected mice. Similarly, protein levels of multiple cytokines and chemokines were significantly higher in the serum and brains of WNV NY99 infected mice. In contrast, we observed significantly higher numbers of innate and adaptive immune cells in the spleens and brains of WNV Eg101 infected mice. Moreover, total number and percentage of IFN-γ and TNF-α producing WNV-specific CD8(+) T cells were also significantly high in WNV Eg101 infected mice.
  
  
  CONCLUSIONS
  Our data demonstrate that induction of virus-specific effector immune cell response limits virus replication and severe WNV disease in Eg101 infected mice. Our data also demonstrate an inverse correlation between leukocyte accumulation and production of pro-inflammatory mediators in WNV-infected mice. Moreover, increased production of pro-inflammatory mediators was associated with high-virus titers and increased mortality in WNV NY99 infected mice.
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, 96813, Hawaii, USA. mukesh@hawaii.edu.|Pacific Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, Hawaii, 96813, USA. mukesh@hawaii.edu.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, 96813, Hawaii, USA. kelsey20@hawaii.edu.|Pacific Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, Hawaii, 96813, USA. kelsey20@hawaii.edu.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Roe
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, 96813, Hawaii, USA. maileo@hawaii.edu.|Pacific Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, Hawaii, 96813, USA. maileo@hawaii.edu.
authors.forename: Maile
authors.initials: M
authors.lastname: O'Connell
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, 96813, Hawaii, USA. nerurkar@hawaii.edu.|Pacific Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, Hawaii, 96813, USA. nerurkar@hawaii.edu.
authors.forename: Vivek R
authors.initials: VR
authors.lastname: Nerurkar
mesh_terms: D000818:Animals; D002469:Cell Separation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D014901:West Nile Fever / Q000276:immunology* / Q000821:virology*; D014902:West Nile virus / Q000235:genetics* / Q000276:immunology*