Characterization and Epidemiology of Viruses Belonging to the African Haemorrhagic Fever group, with Particular Reference to Marburg.

Between July and September 1976, widespread interest on an international scale was directed towards outbreaks of viral haemorrhagic fever which occurred in the southern Sudan and northern Zaire. This thesis is an account of the work carried out by the author with the assistance of three members of the staff of the Special Pathogens Unit at the Microbiological Research Establishment, Porton Down, Salisbxiry. It describes the successful isolation and identification of the aetiologic agent, and also describes the successful transmission of the disease to guinea pigs and monkeys. Characteristic pathological lesions were found in all the experimental animals. The agent produced characteristic intracytoplasmic inclusion bodies in tissue culture which could be detected by both conventional staining and by immunofluorescent techniques. Studies have shown that the agent although morphologically identical to Marburg virus, was antigenically distinct. In concurrence with other principle investigators, the name Ebola virus was proposed. The disease induced in monkeys by infection with Ebola virus was very similar to that which occurs in man. Rhesus and Vervet monkeys therefore seem to be suitable experimental animals in which to study the pathogenesis of the disease and also to evaluate the various aspects of therapy. Infection with the Sudanese strain of the virus appeared to be less virulent in both guinea pigs and monkeys compared with that of the Zaire strain. Rneous monkeys were treated with human leucocyte interferon prophylactics!ly and after experimental infection with the Zaire strain of Ebola virus. Viraemia was delayed and clinically survival appeared to be enhanced. There was no consistent difference in the pathological changes or the outcome ol the infection between the treated and the untreated animals. Epidemiological studies carried out on material from the Sudan, showed antibodies to Ebola virus which were detected by immunofluorescence in 42 of 48 patients in Maridi who had been diagnosed clinically, but only in 6 of 31 patients in Nzara. The possibility of the indirect irnmunofluorescent test not being sufficiently sensitive is discussed. Of Maridi case contacts in hospital and in the local community only 19% had antibodies. Very few of them gave any history of illness indicating that Ebola virus can cause a mild disease or even sub-clinical infection. Detailed virological investigations were carried out on a patient infected with Ebola virus

Human Fatal Zaire Ebola Virus Infection Is Associated with an Aberrant Innate Immunity and with Massive Lymphocyte Apoptosis

Ebolavirus, especially the species Zaïre (ZEBOV), causes a fulminating hemorrhagic fever syndrome resulting in the death of most patients within a few days. In vitro studies and animal models have brought some insight as to the immune responses to ZEBOV infection. However, human immune responses have as yet been poorly investigated, mainly due to the fact that most outbreaks occur in remote areas of central Africa. Published studies, based on small numbers of biological samples have given conflicting results. We studied a unique collection of 50 blood samples obtained during five outbreaks that occurred between 1996 and 2003 in Gabon and Republic of Congo. We measured the plasma levels of 50 soluble factors known to be involved in immune responses to viral diseases. For the first time, using a cell staining technique, we analyzed circulating lymphocytes from ZEBOV-infected patients. We found that fatal outcome in humans is associated with aberrant innate immunity characterized by a “cytokine storm,” with hypersecretion of numerous proinflammatory mediators and by the noteworthy absence of antiviral interferon. The adaptive response is globally suppressed, showing a massive loss of CD4 and CD8 lymphocytes and the immune mediators they produce. These findings may have important pathological and therapeutic implications