An Early Passage Human Isolate of Kyasanur Forest Disease Virus Shows Acute Neuropathology in Experimentally Infected CD-1 Mice.

BACKGROUND: Kyasanur Forest disease virus (KFDV) is a tick-borne Flavivirus that causes a severe illness in humans. Disease spectrum can vary from subclinical infection to fatal cases with hemorrhagic complications. The pathology of KFDV remains incompletely understood. METHODS: This study describes the histopathologic and immunohistochemical findings in experimentally infected infant CD-1 mice with an early passage human KFDV isolate. RESULTS: Acute histological changes were primarily seen in the brain. The spectrum of changes included gliosis, inflammatory response, necrosis, neural loss, and syncytium formation in mid and hind brain structures. Microscopic lesions observed in the liver were mainly necrosis and vacuolation of hepatocytes and in small intestine, prominent epithelial cell necrosis. KFDV antigens could be stained by a sensitive immunohistochemical labeling in the same organs. CONCLUSIONS: Findings from this study are suggestive of neuropathology as the main manifestation of an early passaged human KFDV isolate. Importantly, this suggests that KFDV may be causing primarily a neurologic disease and secondary organ damage could be because of disease pathology per se. The use of primary low passage human isolates and neuropathology profile could also be more apt in developing a challenge model for testing potential antivirals and therapeutic agents.

Comparative pathogenesis of Alkhumra hemorrhagic fever and Kyasanur forest disease viruses in a mouse model.

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.

Clinical study of 100 cases of Kyasanur Forest disease with clinicopathological correlation.

100 cases of Kyasanur Forest Disease were studied clinically and autopsy or postmortem biopsies of various organs were done in 8 cases. 1. Our study showed that KFD passes through 4 stages each lasting for about a week. i.e. a prodromal stage with fever, hypotension hepatomegaly, a stage of complication characterized by haemorrhage, neurological manifestation or bronchopneumonia, a stage of recovery followed by a li stage of fever in some cases. 2. The exact of cause of haemorrhage could not be identified though Disseminated Intravascular Coagulation was suspected. 3. Hypotension in KFD could be of Myocardial origin. 4. Encephalopathy in KFD could be due to a metabolic cause probably of hepatic origin. 5. Lung signs could be due to intraalveolar haemorrhage and secondary infection.

Clinical, clinicopathologic, and hematologic features of Kyasanur Forest disease.

In 1957, a fatal disease occurred among monkeys in a forested area of Shimoga District, Karnataka State, India. Concurrently, there was an outbreak of febrile, occasionally fatal illness among people living in the vicinity. The disease was caused by a new tick-borne flavivirus belonging to the Russian spring-summer encephalitis complex of viruses. The early clinical description of the disease included severe cases with hemorrhagic manifestations, including intermittent epistaxis, hematemesis, melena, and frank blood in the stools. Pathologic and hematologic investigations emphasized similarities with Omsk hemorrhagic fever. Two years later there was a shift in clinical emphasis from hemorrhagic to neurologic complications; this could have resulted from the special interests or bias of the principal investigator or the changing patterns of intercurrent infections. Clinical, clinicopathologic, hematologic, and hemostatic features of Kyasanur Forest disease (KFD) are described, particularly in relation to IgE as a cofactor in the immunopathology of KFD and possibly of other hemorrhagic fevers.