Filoviruses

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Since then, there have been repeated outbreaks of filovirus disease:

The Hot Zone by Richard Preston.

The dramatic and chilling story of an Ebola virus outbreak in a surburban Washington, D.C. laboratory, with descriptions of frightening historical epidemics of rare and lethal viruses. More hair-raising than anything Hollywood could think of, because it's all true. (Amazon.co.uk)

The Coming Plague: Newly Emerging Diseases in a World Out of Balance by Laurie Garrett.

Based on research and interviews with experts in virology, molecular biology, disease ecology, and medicine, an exploration of our battles with microbes examines the current outbreak of infectious diseases and outlines what can be done to prevent the coming plague. (Amazon.co.uk)

Relatively little work has been performed on these viruses because of the difficulties of working with them, but it is now known that:

• No animal reservoir has positively been identified, but fruit and insectivorous bats support replication and circulation of high titers of Ebola virus without necessarily becoming ill.
• Consumption of bushmeat (particularly primates) may be a risk factor.
• Serological surveys in Africa suggest that asymptomatic human infections occur sporadically (i.e. subjects still alive!).

Filoviruses are a major category of emerging viruses.

Particles:

Genome:

The ribonucleoprotein complex consists of the nucleoprotein (NP), the structural proteins VP30, VP35 and the virion-associated RNA dependent RNA polymerase, L. VP35 has an anti-interferon function and can substitute for the function of influenza NS1 for influenza replication (no sequence similarity). VP35/NS1 act as a negative regulators of IFN promoters. The glycoprotein (GP/SGP) is an integral membrane protein and the only glycosylated virion protein, containing both N- & O-linked oligosaccharides. The mature glycoprotein is produced in a complex fashion, involving ribosomal frameshifting, glycosylation & proteolytic cleavage of the precursor into GP1 / GP2, which forms hetero-trimeric spikes in the virus envelope. GP1 is functionally equivalent to influenza HA1/HIV gp120 (receptor binding) and GP2 is to influenza HA2/HIV gp41 (fusion domain) (no sequence simularity between these proteins). In addition to in vivo effects, sGP also increases virus yield and decreases cytopahtic effects of the virus grown in cultured cells.

Folate receptor-alpha is a significant cofactor for cellular entry by Marburg and Ebola viruses (Chan,SY et al. Cell 106(1): 117-26, 2001).

Pathogenesis

The clinical manifestations of Ebola virus infection are severe. The incubation period varies between four & sixteen days. The initial symptoms are a severe frontal & temporal headache, generalised aches & pains, malaise, by the second day the victim will have a fever. Later symptoms include watery diarrhoea, abdominal pain, nausea, vomiting, a dry sore throat, & anorexia. By day seven of the symptoms, the patient will have a maculopapular (small slightly raised spots) rash. At the same time the person will develop thrombocytopenia & haemorrhagic manifestations, particularly in the gastrointestinal tract, & the lungs, but it can occur from any orifice, mucous membrane or skin site. By day twelve the skin starts to peel away from the rash. Ebola causes lesions in almost every organ, although the liver & spleen are the most noticeably affected. Both are darkened & enlarged with signs of necrosis. The cause of death is normally shock, associated with fluid & blood loss into the tissues.

The haemorrhagic and connective tissue complications of the disease are not really understood, but may be related to the fact that the VP40 protein is antigenically related to human cell matrix proteins (abdominal aortic aneurism protein & MFAP-4), leading to autoimmune attack. There are some reports that steroids may be useful in preventing the worse symptoms of Ebola infection. Yang ZY. et al. Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury. Nature Medicine (2000) 6: 886-889.

Why does the immune system not clear the infection? This may be associated with the two forms of the virus glycoprotein. The glycoprotein gene has a translation stop codon in the middle of it, preventing the synthesis of the full length protein. Approximately twenty percent of the mRNA isolated from infected cells had been edited to contain an extra adenosine in a stretch of seven adenosine residues at positions 1019-1026. This causes a frame shift, allowing the synthesis of the full length protein. The larger protein (130Kd - GP) is membrane associated protein, & the truncated version (approximately 60 Kd - SGP) is secreted.

A possible role for SGP is to protect the virus from the immune system as a decoy antigen. However, SGP binds to neutrophils & interferes with their function. Moreover, GP also appears to be immunosuppressive, further interfering with the response to infection. This argues against its use as a vaccine immunogen. Some work has suggested that DNA vaccines may be able to get around this problem (Sullivan NJ. et al. Development of a preventive vaccine for Ebola virus infection in primates. Nature (2000) 408:605-609)

Sullivan N, et al. (2003) Ebola virus pathogenesis: implications for vaccines and therapies. J Virol. 77: 9733-7

Treatment

A recent report suggested that a recombinant anti-clotting agent called rNAPc2 originally derived from parasitic hookworms may be helpful in treating Ebola, and indeed, other haemorrhagic virus infections (Geisbert, T. W. et al. (2003) Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet, 362, 1953-1958).

The effects of various candidate vaccines have been evaluated in both rodents and nonhuman primates, e.g:

• Concentrated, inactivated whole-virion preparation.
• RNA replicon particles derived from an attenuated strain of Venezuelan equine encephalitis virus expressing Ebola virus glycoprotein and nucleoprotein.
• Liposomes containing lipid A and inactivated Ebola virus.
• Recombinant Vaccinia virus expressing Ebola virus glycoprotein.
• Recombinant adenovirus vectors encoding the Ebola glycoprotein (GP) and nucleoprotein (NP): (Sullivan N.J. et al. Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates. Nature 2003 424: 681-684).
• Non-infectious virus-like particles: Warfield KL, et al. Ebola virus-like particles protect from lethal Ebola virus infection. (2003) Proc Natl Acad Sci USA. 100: 15889-94

Ebola: Through the Eyes of the People
Lokela was the first Congolese victim of a new African hemorrhagic disease that became known as Ebola fever. When Sister Lucie dies a few days later, panic erupts and hospitalized patients flee into the forest. With the convent connected to the outside world by a single primitive radio, the mission nuns can only pray and wonder if anyone will act on their cries for help.
(Amazon.co.UK)

• W.H.O. Ebola Information

Search PubMed for all publications on this topic

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