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.

Cross-neutralisation of viruses of the tick-borne encephalitis complex following tick-borne encephalitis vaccination and/or infection

“… 1 Outbreaks of many of the tick-borne flaviviruses are quite common, with TBEV causing an average of 2,600 cases annually in Europe, KFDV causing an average of 400–500 cases per year in India, and AHFV causing approximately 20 cases a year in the Middle East. 4 – 6 The high mortality associated with a number of the members of the TBE complex has led to their classification as risk-group four pathogens in non-endemic countries, requiring work with these viruses to be restricted to Biosafety Level 4 (BSL-4) facilities. 7…”

Al-Khurma Haemorrhagic Fever

“…Mus musculus türünden genetik olarak birbirinin aynı albino farelerin kullanıldığı bu çalışmada, iki virusun doku tropizmlerinin farklı olduğu; KFDV'nin beyinde, AHFV'nin ise viseral organlarda saptandığı; her iki virusun da çoğaldıkları organlarda proinflamatuar sitokinleri indükleye-bildikleri; KFDV infeksiyonunun farelerin tümünü öldürdüğü; AHFV infeksiyonunun ise klinik bulgu oluşturmadığı ve hiçbir hayvanı öldürmediği; AHFV'nin diğer hayvan modellerinde de gözlenen kanamalı ateş bulgularının birçoğunu indükle-mesine karşılık, çok fazla pasajının yapılması yüzünden nö-rovirülansı artan KFDV'nin kanamalı bir hastalığa yol açma özelliğini yitirdiği gözlenmiştir (51).…”

“…KFDV ve AHFV infeksiyonları, uçlarında TBEV ve OHFV infeksiyonlarının olduğu bu klinik yelpazenin ortalarında bir yer tutmaktadır (51). AHFV infeksiyonunun klinik olarak hastaneye yatırılmayı, hatta doktora başvurmayı gerektirmeyecek ölçüde hafif formları da vardır (45).…”

Kyasanur Forest disease virus infection activates human vascular endothelial cells and monocyte-derived dendritic cells

“…Neurological symptoms dominate the second phase of the disease, and pulmonary edema is described as the main cause of death in fatal cases 8 – 10 . Despite the high medical importance of KFD and its alarming epidemiological activity in recent years, its pathogenesis remains largely unstudied 11 . Research on KFD pathogenesis is complicated by the fact that rodent models do not recapitulate human disease; mice infected with KFDV do not exhibit liver and spleen pathology or hemorrhagic signs seen in humans and develop a lethal neuroinfection 11 , 12 .…”