Filoviruses: Scientific Gaps and Prototype Pathogen Recommendation

Abstract

Viruses in the family Filoviridae, including the commonly known Ebola (EBOV) and Marburg (MARV) viruses, can cause severe hemorrhagic fever in humans and nonhuman primates. Sporadic outbreaks of filovirus disease occur in sub-Saharan Africa with reported case fatality rates ranging from 25% to 90%. The high mortality and increasing frequency and magnitude of recent outbreaks along with the increased potential for spread from rural to urban areas highlight the importance of pandemic preparedness for these viruses. Despite their designation as high-priority pathogens, numerous scientific gaps exist in critical areas. In this review, these gaps and an assessment of potential prototype pathogen candidates are presented for this important virus family.

Keywords: Ebola virus; Marburg virus; Sudan virus; filoviruses; prototype pathogens; scientific gaps.

Figure 1.

Filovirus phylogenetic tree. The phylogenetic relationships across the family Filoviridae were established from maximum-likelihood trees generated using genome sequences. This demonstrates the 6 genera of the family. Two of these genera, Ebolavirus and Marburgvirus, contain viruses known to cause disease in humans. For details on phylogenetic tree analysis, see source: https://ictv.global/report/chapter/filoviridae/filoviridae, analysis by Nicholas Di Paola, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD.

Figure 2.

Filovirus genomes. Schematic representation of filovirus genome organization (at scale). Filovirus genomes vary from approximately 15 to 19 kb in length. Common gene organizational structure is 3′-NP-VP35-VP40-GP-VP30-VP24-L-5′ but differs in some species (eg, fish filoviruses XILV and HUJV). Source: https://ictv.global/report/chapter/filoviridae/filoviridae, created by Jiro Wada, National Institutes of Health/National Institute of Allergy and Infectious Diseases/Division of Clinical Research/Integrated Research Facility-Frederick, Fort Detrick, MD.

Figure 3.

Representative filovirus virion. Filovirus particles have a long filamentous morphology with a consistent diameter of about 80 nm and a median length ranging from approximately 800 to 1000 nm. The virions have a central core formed by the ribonucleoprotein complex consisting of the genomic RNA along with the NP, VP35, VP30, and L proteins. This is surrounded by a matrix composed of the VP40 and VP24 proteins and an outer lipid envelope derived from the host cellular plasma membrane. Spikes of the GP protein protrude from the envelope surface. Source: ViralZone www.expasy.org/viralzone, Swiss Institute of Bioinformatics.

Figure 4.

Filovirus replication cycle. Filoviruses attach to target cells through binding of the GP glycoprotein to various host attachment factors (eg, TIM1, DC-SIGN, TLR4), and uptake occurs largely through macropinocytosis. In the endosome, GP is cleaved by cysteine proteases and subsequently binds to the receptor NPC1, initiating membrane fusion and release of the ribonucleoprotein complex into the cytosol. Viral RNA transcripts generated by the polymerase complex (NP, VP35, VP30, and L proteins) from the negative-sense viral RNA genome are translated by host ribosomes to produce viral proteins. Full-length positive-sense antigenomes produced by the polymerase complex serve as a template for synthesis of new negative-sense viral genomes by the replication complex (NP, VP35, and L proteins). Progeny ribonucleoprotein complexes and viral proteins are transported to the plasma membrane, where budding of new viral particles is facilitated by the viral matrix proteins (VP40 and VP24) and host endosomal sorting complex required for transport (ESCRT) complexes. Source: ViralZone www.expasy.org/viralzone, Swiss Institute of Bioinformatics.