Forty-five years of Marburg virus research

Abstract

In 1967, the first reported filovirus hemorrhagic fever outbreak took place in Germany and the former Yugoslavia. The causative agent that was identified during this outbreak, Marburg virus, is one of the most deadly human pathogens. This article provides a comprehensive overview of our current knowledge about Marburg virus disease ranging from ecology to pathogenesis and molecular biology.

Figure 1

Geographic distribution and phylogenetic analysis of Marburg virus. (a) Location of Marburg virus (MARV) infections (circle sizes correspond to reported number of MARV cases) and distribution of the Egyptian fruit bat (Rousettus aegyptiacus) in Africa (www.iucnredlist.org). Outbreak locations (red circles) and sites of initial infection for exported cases of Marburg virus disease (MVD) (purple circles) are shown. (b) Bayesian phylogenetic analysis of full-length MARV genomes isolated from humans and bats. Numbers at the nodes represent posterior probability values. MARV isolates obtained from bats are shown in red. Analysis was performed by S. Carroll and J. Towner, Viral Special Pathogens Branch, CDC Atlanta, GA and represents an updated version of the analysis shown in [22].

Figure 2

Marburg virus reservoir. Egyptian fruit bats (Rousettus aegyptiacus), the putative reservoir of MARV, roosting in the Python cave in Maramagambo Forest, Uganda. Two cases of MVD have been associated with visitors to this cave. Photo courtesy of Bobbie Rae Erickson, Viral Special Pathogens Branch, CDC, Atlanta.

Figure 3

Marburg virus disease outbreak control. (a) Signs used to educate the local population in outbreak areas. Picture taken from [57]. (b) Pictures of the MVD outbreak in Angola, 2005. Above, nurse being sprayed with chlorine while leaving the isolation ward. This illustrates the protective clothing worn by nursing staff. Below, view showing a section of the isolation ward. The ward for confirmed MARV patients is on the left. The solid plastic sheeting used for the outer wall is shown in the distance. Figure and legend modified from [54].

Figure 4

The first electron micrograph of a Marburg virion from 1967. Image courtesy of W. Slenczka, University of Marburg, Germany.

Figure 5

Marburg virion structure and genome organization. Above, schematic of Marburg virion. Below, structure of the MARV genome with transcription signals. The colors of the open reading frames correspond to the colors of the viral proteins. Untranslated regions of the different genes are shown as light grey boxes; intergenic regions (IR) are shown as dark grey lines and the leader and trailer of the genome are colored in black. Transcription start signals (Tc start) are represented by green triangles, while transcription stop signals (Tc stop) are shown as red bars. The sequence of two gene borders (NP/VP35 and VP30/VP24) is shown in 3’ to 5’ orientation, as it occurs in the negative sense RNA genome (MARV Musoke, GenBank accession number: NC_001608). The gene border between VP30 and VP24 contains overlapping transcription signals, with the start signal of VP24 upstream of the stop signal of VP30.

Figure 6

Inhibition of JAK-STAT signaling by filoviruses. MARV VP40 inhibits phosphorylation of Janus kinases and STAT proteins in response to Type I and II IFNs and IL6, preventing downstream signaling. Phosphorylation of STAT proteins is not inhibited by Ebola virus (EBOV). EBOV VP24 interacts with STAT1 and members of the nuclear importin family and prevents nuclear translocation of phosphorylated STAT1.

Figure 7

Replication cycle. MARV initially attaches to target cells via interaction with cell surface molecules (1). Following endocytosis (2), GP₁ is cleaved by endosomal proteases (3) facilitating binding to NPC1, the entry receptor (4). Fusion is mediated in a pH-dependent manner by GP₂. Following release of viral nucleocapsid into the cytosol (5), transcription of the viral genome takes place (6). mRNA is subsequently translated by the host cell machinery (7). Synthesis of GP takes place at the ER and undergoes multiple posttranslational modifications on its way through the classical secretory pathway (8). Positive sense antigenomes are synthesized from the incoming viral genomes (9). These intermediate products then serve as templates to replicate new negative sense genomes (10). After cleavage in the Golgi, GP is transported to multivesicular bodies (MVB) and to the cell membrane where budding takes place (11). Nucleocapsids and VP24 are also recruited to sites of viral budding (12), which is driven by VP40 (13).