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.
Highlights
Kyasanur Forest disease virus (KFDV) and Alkhumra hemorrhagic fever virus (AHFV) are tick-borne flaviviruses that cause severe hemorrhagic disease in humans
The growth patterns of AHFV Zaki-1 and KFDV P9605 were very similar in both the supernatant (Figure 1A) and cell-associated fractions (Figure 1B), whereas AHFV 2003 was more comparable to Omsk hemorrhagic fever virus (OHFV) Guriev (Figures 1A and 1B)
KFDV P9605 was lethal in BALB/c mice, but did not cause disease consistent with a hemorrhagic fever
Summary
Kyasanur Forest disease virus (KFDV) and Alkhumra hemorrhagic fever virus (AHFV) are tick-borne flaviviruses that cause severe hemorrhagic disease in humans. KFDV was first isolated in 1957 [5,6,7] and causes outbreaks with 400–500 cases annually in Karnataka State, western India. KFDV infection is primarily associated with bites from Haemaphysalis ticks [14,15], while AHFV is thought to be transmitted by Ornithodoros savignyi and Hyalomma dromedarii ticks [16,17]. Both viruses have case fatality rates of up to 20% [reviewed in 18], and work with infectious material is restricted to biosafety level 4 (BSL4) laboratories in North America
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