1 Yong Z

Delgado R

Xu L

et al. Distinct cellular interactions of secreted and transmembrane Ebola virus glycoproteins. 2 Baskerville A

Fisher-Hoch SP

Neild GH

Dowsett AB Ultrastructural pathology of experimental Ebola haemorrhagic fever virus infection. 3 Georges AJ

Leroy EM

Renaut AA

et al. Ebola hemorrhagic fever outbreaks in Gabon, 1994–1997: Epidemiologic and health control issues. Ebola virus infection is largely restricted to central Africa (Gabon, the Democratic Republic of the Congo, and Sudan) and is associated with an overwhelming haemorrhagic fever characterised by pyrexia, headache, joint and muscle pains, vomiting and diarrhoea, conjunctivitis, and bleeding. The haemorrhage of Ebola infection seems to be caused by adhesion of viral particles to the endothelial lining of blood vessels via a specialised glycoprotein,the result being infection of, replication in, and damage to, the endothelial cells.The disease is usually fatal.

In today's Lancet, E M Leroy and colleagues report evidence of symptomless Ebola virus infection in 11 individuals who had been in direct contact with affected patients. Since the researchers were unable to detect the virus by culture or with Ebola-specific ELISA, they based their conclusion on the presence of antibodies specific for Ebola in the serum and on the amplification, by PCR, of Ebola genetic sequences from blood cells. Of particular significance was the finding that fragments of positive-stranded RNA could also be amplified, since this amplification indicated that exposure to the negative-stranded RNA virus had resulted in infection associated with viral replication.

4 Morvan JM

Deubel V

Gounon P

et al. Identification of Ebola virus sequences present as RNA or DNA in organs of terrestrial small mammals of the Central African Republic. 5 Clain P

Monroe MC

Nichol ST Ebola virus defective interfering particles and persistent infection. 4 Morvan JM

Deubel V

Gounon P

et al. Identification of Ebola virus sequences present as RNA or DNA in organs of terrestrial small mammals of the Central African Republic. PCR has also been used to amplify fragments of Ebola genes from the organs of apparently healthy shrews and rodents trapped in forest-fringe areas of the Central African Republic.Again in these animals, the virus could not be directly detected by culture or ELISA. One possible explanation for this inability to detect the infection directly is the generation of defective interfering (DI) particles-replicating viral fragments-which contain incomplete copies of the viral genome. These particles probably contribute both to attenuation of viral infection, as their truncated genomes compete with full-length viral genomes for packaging proteins, and to persistence of infection by distracting the immune system. DI particles have been generated in cell lines that have been chronically infected with Ebola,and the electron-micrographic appearance of viral-like structures in the cytoplasm of spleen cells from one of the rodents caught was consistent with that of defective viral neucleocapsids.Irrespective of explanation, the findings reported today imply that a similar carrier state may occur in people who have not been overtly ill.

3 Georges AJ

Leroy EM

Renaut AA

et al. Ebola hemorrhagic fever outbreaks in Gabon, 1994–1997: Epidemiologic and health control issues. 6 Dowell SF

Mukunu R

Ksiazek TG

Khan AS

Rollin PE

Peters CJ Transmission of Ebola hemorrhagic fever: a study of risk factors in family members, Kikwit, Democratic Republic of the Congo, 1995. 7 Bennet D

Brown D Ebola virus. If symptomless Ebola carriage posed a significant risk of infection, evidence of sporadic cases of haemorrhagic fever associated with, but not directly linked to, major outbreaks of Ebola infection should be identifiable by standard epidemiological techniques. Unfortunately, social and political conditions in central Africa seriously impede contact tracing.However, within these limitations, transmission of Ebola has been observed to occur only after close personal contact with affected patients or by exposure to infected body fluids or organs.Every outbreak of Ebola to date has been contained by the institution of standard infection-control measures: effective body disposal, barrier nursing, destruction or sterilisation of contaminated equipment, and the appropriate use of gloves, masks, and gowns.This degree of containment would be virtually impossible if symptom-free carriers posed a significant threat of infection.

8 Baize S

Leroy EM

Georges-Courbot MC

et al. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. One potential explanation for the low infectivity of the Ebola carrier state is the very low levels of virus detectable in these individuals. Although Leroy and colleagues have reliably detected virus by ELISA and isolated it by culture during the first week of symptom-producing infection,they failed to do so in symptomfree contacts. The exquisitely sensitive PCR assay they used to identify fragments of the Ebola virus genome in these contacts involved two rounds of PCR with nested primers-a total of 80 cycles of amplification—so the amount of virus present in the blood of the carriers was likely to have been very low.

The researchers suggest that viral replication in these cases was controlled by effective inflammatory responses triggered 4–6 days after infection. These responses were characterised by detectable concentrations of several cytokines, such as interleukin (IL)-1β, IL-6, and tumour-necrosis factor (TNF). In keeping with their hypothesis, the synthesis of all three of these cytokines is induced by substance P (neurokinin-1) and platelet activating factor, both products of activated endothelial cells.

TNF is secreted by macrophages, monocytes, and T and natural killer (NK) lymphocytes. It enhances phagocytosis and cytotoxicity, and induces the synthesis of IL-1.

IL-1β is the predominant form of IL-1 in man and primes immune responses through its actions on lymphocytes. Its major effect is to stimulate CD4+ T cells to secrete IL-2 and express the IL-2 receptor, although it also promotes proliferation of, and immunoglobulin production by, B cells, activation and proliferation of NK cells, and release of IL-6 from monocytes and activated endothelial cells. In combination, IL-1 and TNF regulate several pathways that maintain the integrity of the endothelium. For example, they inhibit anticoagulatory mechanisms and promote thrombotic processes, thereby reducing local haemorrhage.

IL-6 is the major mediator of the acute-phase reaction, a coordinated systemic response to infection that is characterised by increased numbers of circulating lymphocytes and granulocytes and the secretion of acute-phase proteins from the liver. The acute-phase proteins include complement components and several modulators of coagulation.

8 Baize S

Leroy EM

Georges-Courbot MC

et al. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. The presence of these three cytokines in the blood of symptom-free patients is therefore consistent with a well-targeted innate immune response, triggered by endothelial-cell activation in response to infection, and resulting in effector mechanisms that preserve the integrity of blood vessels and activate the adaptive immune system. An appropriate adaptive immune response to Ebola seems to be important for resolution of infection, since survivors of Ebola haemorrhagic fever can be distinguished from those who later succumb to it by the presence of high titres of antibodies and sustained T-cell responses to viral nucleoprotein.

The significance of the rapid inflammatory response described by Leroy and colleagues remains unclear. Either it is a typical reaction to inoculation with Ebola DI particles or a very small dose of virus; or it may be a means of controlling infection in an individual exposed to an inoculum that would otherwise result in severe illness or death. The latter possibility offers hope of a greater understanding of Ebola pathogenesis and suggests the direction for future therapeutic measures.

Article Info Publication History Identification DOI: https://doi.org/10.1016/S0140-6736(00)02394-1 Copyright © 2000 Elsevier Ltd. All rights reserved. ScienceDirect Access this article on ScienceDirect

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