The nairovirus nairobi sheep disease virus/ganjam virus induces the translocation of protein disulphide isomerase-like oxidoreductases from the endoplasmic reticulum to the cell surface and the extracellular space.

Michael D Baron,Lidia Lasecka

doi:10.1371/journal.pone.0094656

Abstract

Nairobi sheep disease virus (NSDV) of the genus Nairovirus causes a haemorrhagic gastroenteritis in sheep and goats with mortality up to 90%; the virus is found in East and Central Africa, and in India, where the virus is called Ganjam virus. NSDV is closely related to the human pathogen Crimean-Congo haemorrhagic fever virus, which also causes a haemorrhagic disease. As with other nairoviruses, replication of NSDV takes place in the cytoplasm and the new virus particles bud into the Golgi apparatus; however, the effect of viral replication on cellular compartments has not been studied extensively. We have found that the overall structure of the endoplasmic reticulum (ER), the ER-Golgi intermediate compartment and the Golgi were unaffected by infection with NSDV. However, we observed that NSDV infection led to the loss of protein disulphide isomerase (PDI), an oxidoreductase present in the lumen of the endoplasmic reticulum (ER) and which assists during protein folding, from the ER. Further investigation showed that NSDV-infected cells have high levels of PDI at their surface, and PDI is also secreted into the culture medium of infected cells. Another chaperone from the PDI family, ERp57, was found to be similarly affected. Analysis of infected cells and expression of individual viral glycoproteins indicated that the NSDV PreGn glycoprotein is involved in redistribution of these soluble ER oxidoreductases. It has been suggested that extracellular PDI can activate integrins and tissue factor, which are involved respectively in pro-inflammatory responses and disseminated intravascular coagulation, both of which manifest in many viral haemorrhagic fevers. The discovery of enhanced PDI secretion from NSDV-infected cells may be an important finding for understanding the mechanisms underlying the pathogenicity of haemorrhagic nairoviruses.

Highlights

Nairobi sheep disease virus (NSDV) belongs to genus Nairovirus of the family Bunyaviridae and causes a severe disease characterised by fever and haemorrhagic gastroenteritis in sheep and goats with a mortality rate up to 90% in a susceptible population [1,2]
Two isolates of NSDV have been previously described by us [29]: a multiple-times passaged isolate of NSDV from Uganda, which appeared attenuated upon infection of a susceptible animal, and an isolate of Ganjam virus (GV) from India which had been passaged a limited number of times in mouse brain or BHK21 clone 13 cells and which caused haemorrhagic gastroenteritis in sheep upon experimental inoculation
To better understand the replication of nairoviruses we have studied NSDV and its effects on the cellular compartments in infected cells, concentrating on the host cell secretory pathway, which is used by nairoviruses for budding and egress of newly generated virions

Summary

Introduction

Nairobi sheep disease virus (NSDV) belongs to genus Nairovirus of the family Bunyaviridae and causes a severe disease characterised by fever and haemorrhagic gastroenteritis in sheep and goats with a mortality rate up to 90% in a susceptible population [1,2]. NSDV does not appear to be contagious and the virus needs to be transmitted by ticks in natural infection [2]. The virus is primarily transmitted by hard (Ixodid) ticks, with Rhipicephalus appendiculatus being the main vector in Africa [4] and Haemaphysalis intermedia the main vector in India [11,12,13]. Sheep and goats are the only known mammalian reservoir for NSDV [3,4]; other livestock (e.g. cattle, horses) are refractory to the disease [2]. While the virus has a limited effect on animals bred in the enzootic areas due to the development of immunity by these animals while they are still protected by maternal antibodies, NSDV causes large economic losses during transport of animals through enzootic areas or during introduction of new livestock to these areas [2,14,15,16]. There is no safe vaccine [17]

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