Infection and pathogenesis of Huaiyangshan virus (a novel tick-borne bunyavirus) in laboratory rodents

Abstract

A novel tick-borne bunyavirus (Huaiyangshan virus, HYSV), which causes haemorrhagic fever-like disease, has recently been reported in China. So far no animal experiments have been performed to study its pathogenesis. Towards developing an animal model for HYSV fever, newborn and adult mice and rats and golden hamsters were inoculated intracerebrally or intraperitoneally with HYSV. Newborn rats and newborn mice, especially Kunming (KM) mice, appeared highly susceptible. Remarkably, the KM mice that died of the HYSV infection developed large necrotic areas in the liver, while no obvious pathological changes were observed within the other organs. PCR and immunohistochemical analyses of the post-mortem material detected both HYSV antigen and RNA in almost all organs, indicating a systemic infection. Our data demonstrate that HYSV can cause a lethal infection of both newborn mice and newborn rats with apparent pathological damage of the liver. This animal model may help to understand the pathogenesis of the HYSV infection in humans.Viruses of the family Bunyaviridae, which are geographically distributed worldwide, can be classed into five genera: Orthobunyavirus, Hantavirus, Phlebovirus, Nairovirus and Tospovirus (Nichol, 2001;. With the exception of hantaviruses which are hosted and transmitted by mammals (rodents and insectivores) (Jonsson et al., 2010;, all four other genera of viruses are transmitted by arthropods, such as mosquitoes, ticks, sand flies, or thrips (Nichol, 2001;. Among the known viruses, viruses from genera Orthobunyavirus, Hantavirus, Phlebovirus and Nairovirus, can cause human disease, varying from inapparent or mild febrile disease (orthobunyaviruses) to fatal encephalitis, haemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome (hantaviruses), a selflimiting influenza-like illness (mostly) to haemorrhagic fever (rarely) (phleboviruses) and Crimean-Congo hemorrhagic fever (CCHF) (nairoviruses) (Nichol, 2001;.In 2009 and 2010, a haemorrhagic fever-like disease with 15 % mortality emerged in the neighbouring mountain areas of Henan and Hubei provinces, which are located in the central part of China Zhang et al., 2011Zhang et al., , 2012. The illness was characterized by fever, severe malaise, nausea, vomiting and diarrhoea, with haemorrhagic complications in some cases (Zhang et al., , 2012. Yu et al. (2011) reported the disease as severe fever with thrombocytopenia syndrome and the virus as severe fever with thrombocytopenia syndrome virus. As thrombocytopenia is a major feature in nearly all haemorrhagic fever diseases caused by viruses or even by other pathogens such as Rickettsia spp. and Anaplasma phagocytophilum (Sanchez et al., 2004;Srikiatkhachorn et al., 2010;Zhang et al., 2008), we proposed to name the syndrome as Huaiyangshan haemorrhagic fever (HYSHF) and the virus as Huaiyangshan virus (HYSV) according to the geographical origin of the initially reported patients . In 2010, the disease was also found in nine other provinces. In 2011, more than 500 HYSHF cases from th...

The Pathogenesis of Severe Fever with Thrombocytopenia Syndrome Virus Infection in Alpha/Beta Interferon Knockout Mice: Insights into the Pathologic Mechanisms of a New Viral Hemorrhagic Fever

“…A previous study showed that all newborn mice of the Kungming (KM), BALB/c, and C57/BL6 strains died after intracerebral inoculation of SFTSV, while 35 to 50% of newborn mice died after intraperitoneal inoculation of SFTSV (10). However, we demonstrated that newborn CD-1 mice developed signs of illness (lethargy, tremors, and loss of balance) beginning 7 to 8 days p.i., but no mouse died of SFTSV infection.…”

“…The difference in the susceptibility of the mice to SFTSV may be caused by genetic differences in the mice. Previous studies demonstrated that adult mice of the KM, BALB/c, and C57/BL6 strains are not susceptible to SFTSV regardless of the inoculation route (9,10). The only signs of SFTSV infection in C57/BL6 mice are slightly low white blood cell and platelet counts at one time point (7).…”

“…Chen et al observed necrosis and mononuclear cell infiltrations in the liver of mice that died of SFTSV infection, but no obvious pathological changes were observed in other organs (10). Jin et al demonstrated that lymphocyte cellularity of the red pulp was decreased in spleens of SFTSV-infected mice during the first week after inoculation (9).…”

“…The pathology of SFTSV infection and its target cells are unknown, since autopsies have not been performed on humans with fatal cases because of cultural resistance to autopsies and lack of motivation of physicians. SFTSV infection has been studied in animals, including mice and hamsters, but adult animals of these species are not susceptible to SFTSV (9,10). Newborn mice and rats are susceptible to SFTSV infection when they are inoculated intracerebrally.…”

Severe fever with thrombocytopenia syndrome and its pathogen SFTSV

“…or intraperitoneally (i.p) with SFTSV supernatant, and the result showed that all newborn rats and mice were died from i.c. challenge, while 35~50% of newborn mice died from i.p., and no significant clinical manifestation was observed in all adult animals [31]. Hallmark symptoms of thrombocytopenia and leukocytopenia were obtained in C57/BL6 mice through intramuscular inoculation of SFTSV, and if the SFTSVinfected mice were pretreated with immunosuppressive drug mitomycin C, 50% of them would die between day 9 and day 10, and the remaining surviving mice experienced a significant loss of body mass compared with uninfected mice administered mitomycin C in parallel [32].…”