title: Comparative pathogenesis of Alkhumra hemorrhagic fever and Kyasanur forest disease viruses in a mouse model.
abstract: Kyasanur Forest disease virus (KFDV) and Alkhumra hemorrhagic fever virus (AHFV) are genetically closely-related, tick-borne flaviviruses that cause severe, often fatal disease in humans. Flaviviruses in the tick-borne encephalitis (TBE) complex typically cause neurological disease in humans whereas patients infected with KFDV and AHFV predominately present with hemorrhagic fever. A small animal model for KFDV and AHFV to study the pathogenesis and evaluate countermeasures has been lacking mostly due to the need of a high biocontainment laboratory to work with the viruses. To evaluate the utility of an existing mouse model for tick-borne flavivirus pathogenesis, we performed serial sacrifice studies in BALB/c mice infected with either KFDV strain P9605 or AHFV strain Zaki-1. Strikingly, infection with KFDV was completely lethal in mice, while AHFV caused no clinical signs of disease and no animals succumbed to infection. KFDV and high levels of pro-inflammatory cytokines were detected in the brain at later time points, but no virus was found in visceral organs; conversely, AHFV Zaki-1 and elevated levels of cytokines were found in the visceral organs at earlier time points, but were not detected in the brain. While infection with either virus caused a generalized leukopenia, only AHFV Zaki-1 induced hematologic abnormalities in infected animals. Our data suggest that KFDV P9605 may have lost its ability to cause hemorrhagic disease as the result of multiple passages in suckling mouse brains. However, likely by virtue of fewer mouse passages, AHFV Zaki-1 has retained the ability to replicate in visceral organs, cause hematologic abnormalities, and induce pro-inflammatory cytokines without causing overt disease. Given these striking differences, the use of inbred mice and the virus passage history need to be carefully considered in the interpretation of animal studies using these viruses.
authors.affiliation: Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America; Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Bevan
authors.initials: B
authors.lastname: Sawatsky
authors.affiliation: Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America; Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: McAuley
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, Untied States of America; National Institute of Allergy and Infectious Diseases, Integrated Research Facility, Frederick, Maryland, United States of America.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Holbrook
authors.affiliation: Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America; Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Bente
mesh_terms: D000825:Animal Structures / Q000473:pathology; D000818:Animals; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004669:Encephalitis Viruses, Tick-Borne / Q000254:growth & development*; D004675:Encephalitis, Tick-Borne / Q000473:pathology* / Q000821:virology; D005260:Female; D007733:Kyasanur Forest Disease / Q000473:pathology* / Q000821:virology; D008807:Mice, Inbred BALB C; D016019:Survival Analysis
chemical_list: D016207:Cytokines