Filoviruses

Name comes from the Latin: filo = 'threadlike'.

1967: Marburg/Frankfurt, Germany. Laboratory workers preparing primary cell cultures from African green monkeys resulted in an outbreak of a previously unrecognised disease. Highly infectious; 31 cases, 7 deaths (some probably survived due the first theraputic administration(?) of interferon).

1976: Outbreak of a previously unrecognised haemorrhagic fever in Zaire & Sudan 'Ebola disease': 500 diagnosed cases, 460 deaths!

From these two outbreaks, 2 novel viruses (Marburg & Ebola) were isolated - placed in a new family, the Filoviridae:

Year	Location	Cases	Mortality	%	Reference
1971	Zaire	1	0	0	Samaranayake & Peiris, 1996
1976	Sudan	360	150	42	Samaranayake & Peiris, 1996
1976	Zaire	318	280	89	Samaranayake & Peiris, 1996
1977	Zaire	2	2	100	Samaranayake & Peiris, 1996
1979	Sudan	34	22	65	Samaranayake & Peiris, 1996
1989	Reston, USA "The Hot Zone"	4	0	0	Sodhi, 1996
1994	Gabon & Cote d'Ivoire	?	?	?	Breman et al, 1997
1995	Zaire	315	246	78	Breman et al, 1997

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

They are possibly simian viruses, probably widespread throughout Africa, although no animal reservoir has yet been identified.

Serological surveys in Africa suggest that asymptomatic human infections occur sporadically (i.e. subjects still alive!).

Filoviruses are a major category of emerging viruses.

This family of viruses has strong structural & genetic similarities to both Rhabdovirus & the Paramyxovirus.

Particles:

Pleiomorphic, elongated, 80nm diameter x 130-14,000nm long - sometimes straight, but may be curved or hooked - 'U' or '6' shaped. Particles are rounded at one end with a distended swelling at the other. The core has a striated appearance similar to that of Rhabdoviruses.

Genome:

The filovirus genome is s/s, unsegmented, (-)sense RNA, ~19kb. Size varies with length of particle - optimum infectivity for Marburg ~790nm, Ebola ~970nm. Encodes 7 proteins from monocistronic mRNA complementary to vRNA. Signals & expression strategy reminiscent of Rhabdoviruses & Paramyxoviruses, but there are differences, e.g. some filovirus genes overlap:

The ribonucleoprotein complex consists of the nucleoprotein (NP), the structural proteins VP30, VP35 & the polymerase, L. The location of VP40 & VP24 have not been accurately determined, but are thought to be membrane associated. The L protein is the largest protein, & is the virion associated RNA dependent RNA polymerase. The glycoprotein (GP/SGP) is an integral membrane protein & is the only glycosylated virion protein, containing both N- & O-linked oligosaccharides

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 & 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.

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 it's use as a vaccine immunogen. Recent work has suggested that DNA vaccines may be able to get around this problem.