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Chapter 41 : Filoviruses

Author: Mike Bray
Content Type: Reference
Publication Year: 2009

Category: Viruses and Viral Pathogenesis

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Abstract:

The two genera of filoviruses, and , are certainly the most virulent, and are possibly the most mysterious, of the viral pathogens that afflict humans. Person-to-person transmission occurs almost exclusively through direct contact with virus-containing body fluids, and there is no evidence of spread by insect vectors or the respiratory route. The major filoviral matrix protein, VP40, the most abundant protein in the virion, is the driving force behind the assembly and release of new viral particles from infected cells. Both Marburg and Ebola viruses have been recovered from wild African primates, but it is clear that those animals cannot serve as maintenance hosts, because their populations are too small to support the spread of a rapidly lethal disease. Instead, it appears likely that the filoviruses persist through continuous transmission in one or more species of small animals that are widely distributed in central Africa. Filoviruses replicate to high titers in many types of cultured cells, including Vero monkey kidney cells, human umbilical vein endothelial cells, and primary human macrophages. Cultured human macrophages infected with Ebola Zaire virus release the proinflammatory cytokines and chemokines tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, alpha interferon (IFN-1α), and RANTES into the growth medium. Reverse transcription-PCR (RT-PCR) has been found to be more sensitive than antigen-based tests for rapid diagnosis; in the Gulu epidemic, the technique identified infected patients 24 to 48 h earlier than an enzyme-linked immunosorbent assay (ELISA) method.

Citation: Bray M. 2009. Filoviruses, p 923-941. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch41

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Ebola Virus
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Tumor Necrosis Factor alpha
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Ebola Hemorrhagic Fever
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Filoviruses
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Citation: Bray M. 2009. Filoviruses, p 923-941. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch41
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FIGURE 1
Members of an outbreak response team collect a saliva sample for testing by RT-PCR during the epidemic of Marburg hemorrhagic fever in Uige, Angola, in 2005. Saliva testing can accurately identify patients with full-blown filoviral hemorrhagic fever, but it is less sensitive than blood testing for detecting cases early in the disease course. (Courtesy of Steve Jones, Arthur Marx, and Ute Stroher, Public Health Agency of Canada.)
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FIGURE 1

Members of an outbreak response team collect a saliva sample for testing by RT-PCR during the epidemic of Marburg hemorrhagic fever in Uige, Angola, in 2005. Saliva testing can accurately identify patients with full-blown filoviral hemorrhagic fever, but it is less sensitive than blood testing for detecting cases early in the disease course. (Courtesy of Steve Jones, Arthur Marx, and Ute Stroher, Public Health Agency of Canada.)

Citation: Bray M. 2009. Filoviruses, p 923-941. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch41
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FIGURE 2
(A) Negative-contrast electron micrograph of Ebola Zaire virus virions, concentrated by centrifugation from a Vero cell supernatant and dried onto a grid (magnification, ×17,000); (B) transmission electron micrograph of nucleocapsids in a cytoplasmic inclusion body in an infected hepatocyte; (C) scanning electron micrograph of Ebola Zaire virus virions budding from the surface of an infected primary human umbilical vein endothelial cell. (Courtesy of Tom Geisbert, USAMRIID.)
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FIGURE 2

(A) Negative-contrast electron micrograph of Ebola Zaire virus virions, concentrated by centrifugation from a Vero cell supernatant and dried onto a grid (magnification, ×17,000); (B) transmission electron micrograph of nucleocapsids in a cytoplasmic inclusion body in an infected hepatocyte; (C) scanning electron micrograph of Ebola Zaire virus virions budding from the surface of an infected primary human umbilical vein endothelial cell. (Courtesy of Tom Geisbert, USAMRIID.)

Citation: Bray M. 2009. Filoviruses, p 923-941. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch41
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FIGURE 3
(A) Diagram of a filovirus virion, showing the single-stranded negative-sense RNA genome with its associated nucleocapsid proteins, enveloped in a lipid bilayer bearing GP spikes. The NP and VP30 bind to virion RNA to make up the nucleocapsid, and VP35 and the polymerase (L protein) join them in forming a replication complex. Matrix proteins VP24 and VP40 link the nucleocapsid to GP embedded in the lipid membrane bilayer. (B) Schematic representation of the genomes of Marburg and Ebola viruses. The seven genes encoding viral structural proteins are drawn roughly to scale; coding regions are shaded. Most genes are separated by intergenic regions (IR), but some overlap in short sequences containing a conserved transcriptional signal. Indicated for Ebola virus is the “editing site” at which transcription of the GP gene generates either a full-length membrane-anchored GP or a nonstructural sGP, depending upon whether the polymerase does or does not add a single uncoded adenosine.
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Image of FIGURE 3
FIGURE 3

(A) Diagram of a filovirus virion, showing the single-stranded negative-sense RNA genome with its associated nucleocapsid proteins, enveloped in a lipid bilayer bearing GP spikes. The NP and VP30 bind to virion RNA to make up the nucleocapsid, and VP35 and the polymerase (L protein) join them in forming a replication complex. Matrix proteins VP24 and VP40 link the nucleocapsid to GP embedded in the lipid membrane bilayer. (B) Schematic representation of the genomes of Marburg and Ebola viruses. The seven genes encoding viral structural proteins are drawn roughly to scale; coding regions are shaded. Most genes are separated by intergenic regions (IR), but some overlap in short sequences containing a conserved transcriptional signal. Indicated for Ebola virus is the “editing site” at which transcription of the GP gene generates either a full-length membrane-anchored GP or a nonstructural sGP, depending upon whether the polymerase does or does not add a single uncoded adenosine.

Citation: Bray M. 2009. Filoviruses, p 923-941. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch41
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FIGURE 4
(A) In situ hybridization of viral RNA in marginal-zone macrophages of the spleen of a mouse, day 3 after infection with mouse-adapted Ebola Zaire virus. (Courtesy of Tammy Gibb, USAMRIID.) (B) Multifocal necrosis in the liver of a mouse 4 days after infection with the same virus. Some infected hepatocytes contain large acidophilic viral inclusions (arrowhead). (Courtesy of Kelly Davis, USAMRIID.)
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FIGURE 4

(A) In situ hybridization of viral RNA in marginal-zone macrophages of the spleen of a mouse, day 3 after infection with mouse-adapted Ebola Zaire virus. (Courtesy of Tammy Gibb, USAMRIID.) (B) Multifocal necrosis in the liver of a mouse 4 days after infection with the same virus. Some infected hepatocytes contain large acidophilic viral inclusions (arrowhead). (Courtesy of Kelly Davis, USAMRIID.)

Citation: Bray M. 2009. Filoviruses, p 923-941. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch41
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FIGURE 5
Immunoperoxidase-stained skin biopsy sample from a fatal case of Ebola Zaire virus infection in the 1995 Kikwit outbreak. Viral antigen is seen in fibroblasts and endothelial cells, outlining small vessels (arrowhead). (Courtesy of Sherif Zaki, CDC.)
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Image of FIGURE 5
FIGURE 5

Immunoperoxidase-stained skin biopsy sample from a fatal case of Ebola Zaire virus infection in the 1995 Kikwit outbreak. Viral antigen is seen in fibroblasts and endothelial cells, outlining small vessels (arrowhead). (Courtesy of Sherif Zaki, CDC.)

Citation: Bray M. 2009. Filoviruses, p 923-941. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch41
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FIGURE 6
Pathogenetic mechanisms of filoviral hemorrhagic fever, based on data from human cases and studies of lethal infection of rodents and nonhuman primates. Macrophages are the primary site of viral replication. Suppression of type I interferon responses permits rapid dissemination from the initial site of infection to macrophages and dendritic cells in the spleen, lymph nodes, and other lymphoid tissues and to hepatocytes and parenchymal cells of other organs, resulting in extensive necrosis. At the same time, the release of proinflammatory cytokines, chemokines, nitric oxide, and other mediators and the production of cell surface tissue factor by infected macrophages cause a diffuse increase in vascular permeability and DIC, producing a systemic inflammatory syndrome resembling septic shock. Lymphocytes remain uninfected but undergo programmed cell death, apparently brought about through the proapoptoptic effects of inflammatory mediators and a loss of normal support signals from infected dendritic cells. The massive loss of lymphocytes and dendritic cells creates a state of “immune paralysis” in the terminal phase of illness.
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Image of FIGURE 6
FIGURE 6

Pathogenetic mechanisms of filoviral hemorrhagic fever, based on data from human cases and studies of lethal infection of rodents and nonhuman primates. Macrophages are the primary site of viral replication. Suppression of type I interferon responses permits rapid dissemination from the initial site of infection to macrophages and dendritic cells in the spleen, lymph nodes, and other lymphoid tissues and to hepatocytes and parenchymal cells of other organs, resulting in extensive necrosis. At the same time, the release of proinflammatory cytokines, chemokines, nitric oxide, and other mediators and the production of cell surface tissue factor by infected macrophages cause a diffuse increase in vascular permeability and DIC, producing a systemic inflammatory syndrome resembling septic shock. Lymphocytes remain uninfected but undergo programmed cell death, apparently brought about through the proapoptoptic effects of inflammatory mediators and a loss of normal support signals from infected dendritic cells. The massive loss of lymphocytes and dendritic cells creates a state of “immune paralysis” in the terminal phase of illness.

Citation: Bray M. 2009. Filoviruses, p 923-941. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch41
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FIGURE 7
Extensive desquamation of the forearm and hand of an Ebola Sudan virus survivor, 3 weeks after disease onset, Gulu, Uganda, 2000. (Courtesy of Dan Bausch, Tulane University.)
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Image of FIGURE 7
FIGURE 7

Extensive desquamation of the forearm and hand of an Ebola Sudan virus survivor, 3 weeks after disease onset, Gulu, Uganda, 2000. (Courtesy of Dan Bausch, Tulane University.)

Citation: Bray M. 2009. Filoviruses, p 923-941. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch41
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Tables

Filoviruses
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Citation: Bray M. 2009. Filoviruses, p 923-941. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch41
/content/10.1128/9781555815981.ch41.ch41tab01
TABLE 1
Known cases and epidemics of filoviral hemorrhagic fever
Generic image for table
TABLE 1

Known cases and epidemics of filoviral hemorrhagic fever

Citation: Bray M. 2009. Filoviruses, p 923-941. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch41

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