Kyasanur Forest Disease Virus Infection in Mice Is Associated with Higher Morbidity and Mortality than Infection with the Closely Related Alkhurma Hemorrhagic Fever Virus

Abstract

BackgroundKyasanur Forest disease virus (KFDV) and Alkhurma hemorrhagic fever virus (AHFV) are closely related members of the Flavivirus genus and are important causes of human disease in India and the Arabian Peninsula, respectively. Despite high genetic similarity, the viruses have distinctly different host ranges and ecologies. Human cases of KFDV or AHFV develop a spectrum of disease syndromes ranging from liver pathology to neurologic disease. Case reports suggest KFDV is more commonly associated with hepatic and gastrointestinal manifestations whereas AHFV is more commonly associated with neurologic disease.Methodology/Principal FindingsInoculation of three immunocompetent laboratory mouse strains revealed that KFDV was consistently more lethal than AHFV. In subsequent studies utilizing C57BL/6J mice, we demonstrated that KFDV infection was associated with higher viral loads and significantly higher mortality. KFDV-infected mice rapidly developed more severe disease than AHFV-infected mice, as evidenced by significant abnormalities on clinical chemistry panels and more severe pathology in the brain and gastrointestinal tract.Conclusions/SignificanceInfections of C57BL/6J mice with KFDV or AHFV resulted in clinical disease syndromes that closely approximate the diseases seen in human cases. Despite high genetic similarity, there were clear differences in survival, viral kinetics, clinical chemistry data and histology. These results suggest that distinct mouse models for AHFV and KFDV are necessary in order to gain a better understanding of the unique pathogenesis of each virus, as well as to provide platforms for testing promising vaccines and therapeutics.

Mining the Alkhumra Hemorrhagic Fever Virus Genomes in 2015

“…Discovery of the virus was considered an important event because flaviviruses are responsible for hemorrhagic fever in humans and had been isolated only in Siberia (Omsk hemorrhagic fever virus) and India (Kyasanur Forest disease virus) (Charrel et al 2005). Alkhumra hemorrhagic fever virus was confirmed to be a tick-borne flavivirus similar to Kyasanur Forest disease virus in India (Charrel et al 2005, Dodd et al 2014.…”

“…Epidemiological data suggest that Alkhumra hemorrhagic fever virus is transmitted to humans from animals such as sheep (Ovis aries L.), goats (Capra aegagrus hircus (L.)), or camels (Camelus dromedarius L.); by direct contact with the animals or by mosquito or tick bites (Madani 2005, Charrel et al 2007, Madani et al 2011, although no disease has been reported in livestock or other animals (Dodd et al 2014). Alkhumra hemorrhagic fever virus was isolated from an Ornithodoros tick at Jeddah (Charrel et al 2007) and sand tampan tick, Ornithodoros savignyi (Audouin), and camel tick, Hyalomma dromedarii Koch, at Najran (Mahdi et al 2011).…”

Al-Khurma Haemorrhagic Fever

“…C57BL/6J fareleriyle sürdürülen çalışmada KFDV infeksiyonunda viral yükün ve mortalitenin daha yüksek olduğu gösterilmiştir. KFDV ile infekte farelerde hızla daha ağır bir hastalık gelişmiş; buna biyokimyasal laboratuvar bulgularındaki anormalliklerle birlikte beyin ve gastrointestinal sistemdeki ağır patoloji de eşlik etmiştir (52).…”

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

“…This has been the major reason for studying the pathology of KFDV infection in detail in both natural and experimental infections. More importantly, such studies including two recent ones have provided important findings toward the understanding of KFDV pathogenesis (Dodd et al 2014, Sawatsky et al 2014. In this study, we examined the nature of histopathologic lesions caused by a primary human isolate of KFDV in laboratory mice.…”

“…It is difficult to carry out such studies now because of the high biosafety and containment level requirement for KFDV as this has been classified as a category 4 agent and requires a BSL4 laboratory for experimental handling. In 2014, two studies reported on the comparative pathology in inbred laboratory mice experimentally infected with KFDV and Alkhurma Hemorrhagic fever virus, a virus genetically related to KFDV (Dodd et al 2014, Swatsky 2014. Two important points emerged from these studies.…”