Phlebovirus
Phlebovirus is one of twenty genera of the family Phenuiviridae in the order Bunyavirales. The genus contains 66 species.[1] It derives its name from Phlebotominae, the vectors of member species Naples phlebovirus, which is said to be ultimately from the Greek phlebos, meaning "vein".[2] The proper word for "vein" in ancient Greek is however phleps (φλέψ).[3]
Phleboviruses are viruses with a negative-sense RNA genome consisting of three segments. The small segment (S) codes for the viral N protein and a non structural protein, NSs via an ambisense coding strategy. The medium-sized segment (M) codes for a precursor of the viral glycoproteins and non-structural components. The product of the largest segment (L) is the viral RNA-dependent RNA polymerase.[4]
The Phlebovirus replicates in a 7 step process. First, the cellular attachment is driven through the glycoprotein interactions with host cells. Examples of this are Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Non-Integrin (DC-SIGN), heparan sulfate (HS), or Non-Muscle Myosin Heavy Chain (NMMHC-IIA). Second, in the late endosome, the low pH causes fusion activity in the membrane of the Gc protein. Uukuniemi virus (UUKV) penetration is promoted by the expression of vesicle-associated membrane protein 3 (VAMP3). Additionally, the fusion of Rift Valley fever virus (RVFV) in late endosomes is inhibited by the interferon-induced transmembrane proteins 2 and 3 (IFITIM2 and IFITIM3). Third,the viral and endosomal membranes are fused to allow for the release of the viral ribonucleoprotein complexes into the cytoplasm (Also the site of viral transcription and replication). Fourth, the precursor protein, Gn/Gc, is translated at the rough endoplasmic reticulum (ER). This precursor protein is cleaved by signal peptidase. Synthesis of the viral nucleoprotein and viral polymerase in the cytoplasm combines with the newly formed genomic RNA (gRNA) ribonucleic protein complexes (RNP). Fifth, two ER chaperones, binding immunoglobulin protein (BiP) and calnexin, are required to ensure proper folding of GN/Gc. Gn/Gc are similarly catalyzed by protein-disulfide-isomerase through the formation of disulfide bonds. At the same time, calreticulin prevents any misfolded Gn/Gc from being exported to the Golgi. Sixth,The correctly folded Gn/Gc heterodimers are transported to the Golgi apparatus. The cytoplasmic tails of Gn in the budding process associate with RNPs during this time. Seventh, once the budding of the new virus particles is completed, vesicles that contain the virus are transported to the plasma membrane to be released by exocytosis.[5]
A study of the family Bunyaviridaeshowed that bunyavirus particles are pleomorphic. This known fact cased some surprise when studies showed that UUKKV and RVFV particles are spherically shaped and highly ordered. The configuration of Gn and Gc proteins in the viral envelope imposes the order of the particle. The viral envelope forms an icosahedral lattice with a triangulation number of 12. Also included in the lattice composition are 110 hexametric and 12 pentameric capsomeres. For RVFV in particular, 720 Gn/Gc heterodimers are included in the capsomeres. In these cases, Gn forms the spikes of the capsomere while Gc is closer to the lipid membrane, thus placing it underneath. The pH surrounding the capsomere ultimately determines its shape. This is largely due to protonation triggering conformational changes in Gc, commonly included with membrane fusion.An assembly model for the RVFV envelope has been proposed which consists of Gc dimers positioned horizontally with respect to the viral membrane. This is known because the RVFV Gc ectodomain is crystallized as a dimer. This is opposed to the virion interior of bunyaviruses which has no matrix protein, and thus, has no defining organization. This means that on the virion surface, the Gc and Gn proteins must be present in a highly ordered placement.the Gc and Gn proteins must be present in a highly ordered placement.the Gc and Gn proteins must be present in a highly ordered placement.
