The Lassa virus is the pathogen responsible for Lassa fever, a viral hemorrhagic fever endemic to West Africa. It infects hundreds of thousands of people annually, causing thousands of deaths. Understanding the virus’s physical and genetic makeup is fundamental to developing medical interventions against the disease.
Overall Viral Architecture
The Lassa virus particle, or virion, is a member of the Arenaviridae family. These virions are spherical but can be variable in shape, a quality known as pleomorphism. They measure approximately 110 to 130 nanometers in diameter. The structure consists of a central core that houses the genetic material, all enclosed within a lipid bilayer known as an envelope.
A distinct feature of arenaviruses is visible under an electron microscope. During their formation process, the virus particles envelop ribosomes from the host cell they have infected. These captured ribosomes appear as small, grainy dots inside the virion. This characteristic gives the virus a “sandy” look, which is the origin of the name Arenaviridae, derived from the Latin word ‘arena’ for sand.
The Viral Envelope and Surface Glycoproteins
The outermost boundary of the Lassa virus is its envelope, a lipid bilayer acquired from the host cell membrane as new virus particles are formed and released. Embedded within this lipid layer are numerous spikes, which are glycoprotein complexes (GPC) that protrude from the viral surface. These structures are the virus’s primary tool for interacting with host cells.
The journey of the GPC begins as a single, large precursor protein that is synthesized inside the host cell. This precursor undergoes a multi-step processing sequence to become functional. It is first cleaved to produce an initial glycoprotein, GP-C, and a stable signal peptide (SSP). The SSP remains associated with the complex, playing a structural role in stabilizing the final assembly on the viral surface.
The GP-C protein is cleaved a second time by a host cell enzyme called SKI-1/S1P. This cut divides GP-C into two distinct subunits: GP1 and GP2. The GP1 subunit sits on the exterior of the spike and is responsible for finding and binding to a specific receptor on the surface of a host cell, known as alpha-dystroglycan.
Once GP1 has locked onto the receptor, the GP2 subunit, which is a transmembrane protein anchored in the viral envelope, initiates the next step. GP2 mediates the fusion of the viral envelope with the host cell’s membrane. This creates an opening through which the virus’s internal contents can enter the cell and begin replication.
Genetic Material and Core Proteins
Inside the viral envelope, the Lassa virus genome is organized into two separate segments of single-stranded RNA, known as the Large (L) and Small (S) segments. This genetic material carries the blueprint for creating new virus particles. The virus employs an “ambisense” coding strategy, meaning each RNA segment contains two genes that are oriented in opposite directions. This arrangement allows four different proteins to be encoded from just two pieces of RNA.
The S segment of the genome codes for two proteins: the nucleoprotein (NP) and the glycoprotein precursor (GPC), which assembles into the surface spikes. The NP is a structural protein that performs a protective function. It coats the viral RNA, wrapping it into a stable structure called a ribonucleoprotein complex (RNP). This NP coating shields the RNA from being degraded by host cell enzymes and helps it evade detection by the cell’s innate immune system.
The L segment is responsible for producing the L protein and the Z protein. The L protein is a large enzyme that acts as the RNA-dependent RNA polymerase. This polymerase is the machine that reads the viral RNA and carries out both replication, to make more copies of the genome, and transcription, to produce messenger RNA for protein synthesis. The Z protein is a matrix protein that lines the inner surface of the viral envelope and plays a part in regulating the polymerase and organizing the assembly and budding of new virus particles from the host cell.
Structural Insights for Medical Countermeasures
A detailed understanding of the Lassa virus’s structure directly informs the development of vaccines and antiviral drugs. The components of the virus provide specific targets for medical intervention. By mapping out the architecture of the virion and the function of its proteins, scientists can design targeted strategies to neutralize the pathogen.
Vaccine development efforts focus on the glycoprotein spikes on the viral envelope. The GP1 and GP2 proteins are the parts of the virus that the human immune system first recognizes. Knowledge of their three-dimensional shape allows researchers to design vaccine candidates that present these proteins to the body in a way that stimulates a protective antibody response. These antibodies can then block the GP1 subunit from binding to host cells, preventing infection.
The internal machinery of the virus offers another set of targets for antiviral drugs. The L protein, with its RNA-dependent RNA polymerase function, is a target. Drugs can be developed to inhibit this enzyme, stopping the virus from replicating its genome. Other drug strategies include designing molecules that block the interaction between the GP1 protein and its alpha-dystroglycan receptor, thereby preventing the virus from entering host cells.