Filovirus

What is Filovirus?

Filoviruses get their name because their viral particles take a filamentous or thread-like morphology and belong to the Filoviridae family. Filovirus is a single-stranded RNA virus belonging to the order Virida, which was first observed by electron microscopy in clinical specimens and cell cultures in 1971. These viruses primarily infect vertebrates and are the main causative agent of severe haemorrhagic fevers, such as Ebola haemorrhagic fever. Severe haemorrhagic fever is a highly contagious and fatal disease that can cause severe outbreaks and affect public health. The mode of transmission and high pathogenicity of filoviruses have made them important subjects of research in the field of global health. Effective surveillance, prevention, and treatment strategies are essential to control the disease caused by filoviruses, particularly in preventing them from causing large-scale outbreaks and reducing mortality.

Category of Filovirus

Filoviridae is mainly divided into two genera, Marburg virus and Ebola virus. Both virus genera are extremely contagious and extremely harmful to humans.

Ebola virus

The Ebola virus (EBOV) is part of the genus Filoviridae, a non-segmental, single-stranded negative-strand RNA virus. There are five viruses in the genus Ebolavirus. Ebola is a generic term for several viruses in the genus Virus, and it is also a virulent infectious disease that causes Ebola haemorrhagic fever in humans and primates, with a high fatality rate.

Marburg virus

There is only one virus in the genus Marburgvirus, which is Lake Victoria Marburgvirus. Marburg virus is a virulent virus that causes viral hemorrhagic fevers. The virus can be transmitted by bats and can also be transmitted to humans by monkeys. When a human body is infected, it is possible that the virus can be transmitted to other people in the body as well as body fluids and secretions. After being infected with this virus, a range of clinical signs of hemorrhagic fevers may appear.

Filovirus structure

Filovirus virions have complex structures with envelopes, nucleocapsid, polymerase complexes, and matrixes. The virions are encapsulated in the mantle. The shape of the virus is filamentous, or branched and multimorphic, or U-shaped, 6-shaped, or round (especially after purification), the diameter of the virus is about 80 nm, up to 1400 nm long, and the length of the purified virus may reach 790-970 nm. The surface has the shape of a nodulous protrusion, scattered in a lipid bilayer membrane.

Studies have shown that EBOV and MARV virions are filamentous, with a typical length of ∼970 nm. The spiral nucleocapsid is located on the central axis of the filamentous granules and has a host-derived lipid bilayer envelope and an inner layer VP40 arranged below the envelope (Fig.1). VP40 interacts with lipid membranes in the form of butterfly-like dimers, with two N-terminal domains and C-terminal basic plaques interacting with lipid membranes. The virions are covered with GPs, consisting of GP1 and GP2, which form spike structures on the surface. VP40 produces only filamentous virus-like particles, which are essential for the integration of nucleocapsids into filamentous virions, suggesting that VP40 plays a central role in viral particle formation.

Fig.1 The overall structure of the filovirus particle. (Hu Shangfan, 2023)

Filovirus replication

The replication cycle of a filovirus in a host cell consists of multiple steps, from entry, uncoating, genome transcription, and replication to assembly, virion formation, and budding. Filovirus particle entry is mediated by GP or phosphatidylserine in the extra-envelope leaflet of the virion. After membrane fusion, the nucleocapsid within the virion is released into the cytoplasm (uncoating), where polymerase L begins to transcribe viral genes into mRNA with the help of VP35. Nucleocapsids carry out transcription and replication of the viral genome. After transcription, the polymerase adds a 5ʹcap and a poly(A) tail to the nascent mRNA, which is translated by the host's cellular translation machinery. During antisense RNA replication, viral polymerase synthesizes positive and anti-genome, and in turn, the anti-genome acts as a template for the synthesis of negative sense RNA genome. The nucleocapsid component is assembled in inclusion bodies within the cytoplasm. In addition, VP40 promotes nucleocapsid transport to the plasma membrane, where all viral structural components assemble to form progeny virions. Finally, VP40 utilizes the endosomal sorting complex (ESCRT) pathway required for transport to bud progeny virions from virus-infected cells (Fig.2).

Fig.2 Procedure diagram of the filovirus replication cycle. (Hu Shangfan, 2023)

Filovirus treatment

Treatment after Filovirus infection focuses on supportive care and symptom management, with the goal of maintaining the patient's vital signs, controlling symptoms, and preventing complications.

Supportive care

Fluid and electrolyte management: By monitoring the patient's fluid intake and discharge, adjusting the infusion speed and composition, and ensuring that the patient maintains proper hydration and electrolyte balance, to prevent dehydration and electrolyte imbalance, and avoid damage to the function of vital organs such as the heart and kidneys.

Blood pressure management: By using appropriate medications and fluids to regulate the patient's blood pressure level, ensure stable blood pressure, prevent shock and other complications caused by hypotension or hypertension, and protect the normal functioning of the cardiovascular and cerebrovascular system.

Blood transfusions and fluids: In the case of severe bleeding or anemia, timely transfusion of whole blood, red blood cells, plasma or other blood products to replenish blood loss, restore blood volume, maintain blood oxygen-carrying capacity and coagulation function.

Oxygen support: According to the patient's oxygenation, provide oxygen therapy with appropriate concentrations to maintain normal oxygen saturation, ensure that tissues and organs receive sufficient oxygen supply, and prevent tissue damage and metabolic disorders caused by hypoxia.

Nutritional support: Ensure that the patient is getting enough nutrients to support the body's recovery.

Antiviral therapy

Experimental treatments: Some antiviral compounds and treatments are being studied and experimented, such as Remdesivir, BCX 4430 hydrochloride, EBOV-GP-IN-1, etc. These compounds have shown efficacy in some clinical trials, especially in the context of specific viral infections. However, the efficacy and safety of these drugs still need to be further studied and rigorously verified.

Monoclonal antibodies: The use of monoclonal antibodies against the Ebola virus, such as ZMapp, REGN-EB3, and mAb114, has shown efficacy in some cases.

Plasma therapy: The use of convalescent plasma extracted from recovered patients and containing antibodies against the virus can help newly infected patients fight the virus.

Through a series of research experiments, researchers have identified small-molecule inhibitors that can inhibit filoviruses. There is evidence that the glycoprotein folding of many filoviruses is more dependent on the protein-folding calcapectin pathway than most host glycoproteins. Therefore, small molecules that inhibit this pathway are expected to have selective antiviral effects.

References

• Beniac, Daniel R., et al., Filovirus filament proteins. Virus Protein and Nucleoprotein Complexes (2018): 73-94.
• Hu, Shangfan, and Takeshi Noda. Filovirus helical nucleocapsid structures. Microscopy 72.3 (2023): 178-190.

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