title: Impaired virus clearance, compromised immune response and increased mortality in type 2 diabetic mice infected with West Nile virus.
abstract: Clinicoepidemiological data suggest that type 2 diabetes is associated with increased risk of West Nile virus encephalitis (WNVE). However, no experimental studies have elucidated the role of diabetes in WNV neuropathogenesis. Herein, we employed the db/db mouse model to understand WNV immunopathogenesis in diabetics. Nine-week old C57BL/6 WT and db/db mice were inoculated with WNV and mortality, virus burden in the periphery and brain, and antiviral defense responses were analyzed. db/db mice were highly susceptible to WNV disease, exhibited increased tissue tropism and mortality than the wild-type mice, and were unable to clear the infection. Increased and sustained WNV replication was observed in the serum, peripheral tissues and brain of db/db mice, and heightened virus replication in the periphery was correlated with enhanced neuroinvasion and replication of WNV in the brain. WNV infection in db/db mice was associated with enhanced inflammatory response and compromised antiviral immune response characterized by delayed induction of IFN-α, and significantly reduced concentrations of WNV-specific IgM and IgG antibodies. The compromised immune response in db/db mice correlated with increased viremia. These data suggest that delayed immune response coupled with failure to clear the virus leads to increased mortality in db/db mice. In conclusion, this study provides unique mechanistic insight into the immunopathogenesis of WNVE observed in diabetics and can be used to develop therapeutics for the management of WNVE among diabetic patients.
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Kumar
authors.forename: Kelsey
authors.initials: K
authors.lastname: Roe
authors.forename: Pratibha V
authors.initials: PV
authors.lastname: Nerurkar
authors.forename: Madhuri
authors.initials: M
authors.lastname: Namekar
authors.forename: Beverly
authors.initials: B
authors.lastname: Orillo
authors.forename: Saguna
authors.initials: S
authors.lastname: Verma
authors.forename: Vivek R
authors.initials: VR
authors.lastname: Nerurkar
mesh_terms: D000273:Adipose Tissue / Q000473:pathology / Q000821:virology; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D001835:Body Weight; D001921:Brain / Q000473:pathology / Q000821:virology; D018925:Chemokines / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000276:immunology* / Q000821:virology*; D004198:Disease Susceptibility / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000821:virology; D018149:Glucose Intolerance / Q000097:blood / Q000150:complications / Q000276:immunology / Q000821:virology; D005951:Glucose Tolerance Test; D007109:Immunity / Q000276:immunology*; D016898:Interferon-alpha / Q000097:blood; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D013045:Species Specificity; D016019:Survival Analysis; D019562:Viral Load; D014779:Virus Replication; D014901:West Nile Fever / Q000097:blood / Q000150:complications / Q000276:immunology* / Q000821:virology*; D014902:West Nile virus / Q000276:immunology* / Q000502:physiology
chemical_list: D000914:Antibodies, Viral; D018925:Chemokines; D016898:Interferon-alpha