Entry of Phenuiviruses into Mammalian Host Cells

Abstract

Phenuiviridae is a large family of arthropod-borne viruses with over 100 species worldwide. Several cause severe diseases in both humans and livestock. Global warming and the apparent geographical expansion of arthropod vectors are good reasons to seriously consider these viruses potential agents of emerging diseases. With an increasing frequency and number of epidemics, some phenuiviruses represent a global threat to public and veterinary health. This review focuses on the early stage of phenuivirus infection in mammalian host cells. We address current knowledge on each step of the cell entry process, from virus binding to penetration into the cytosol. Virus receptors, endocytosis, and fusion mechanisms are discussed in light of the most recent progress on the entry of banda-, phlebo-, and uukuviruses, which together constitute the three prominent genera in the Phenuiviridae family.

Keywords: Heartland; RNA virus; Rift; SFTSV; Toscana; Uukuniemi; arbovirus; arthropod; bandavirus; cell entry; emerging virus; endocytosis; fusion; phlebovirus; receptor; uukuvirus.

Figure 1

Phenuiviral particles and the glycoproteins G_N and G_C. (a) Schematic representation of a phenuiviral particle. The three viral genomic RNA segments are named according to their size: S (small), M (medium), and L (large). (b) Proteolytic processing of the phenuivirus M polypeptide precursor. The M precursor and the glycoproteins G_N and G_C can vary greatly among phenuiviral species. In addition to G_N and G_C, some phenuiviruses encode an additional nonstructural protein, NSm. Arrow heads indicate the cleavage sites by host cell proteases within the precursor. The position of the fusion peptide is given based on the crystal structure of the Rift Valley fever virus (RVFV) glycoprotein G_C [39]. (c) Arrangement of G_N and G_C glycoproteins on the surface of phenuiviral particles. Electron cryo-tomography analysis of RVFV [36,37] and Uukuniemi virus (UUKV) [38] viral particles shows an icosahedral lattice with an atypical T = 12 triangulation.

Figure 2

Phenuivirus endocytosis and intracellular trafficking. The internalization of phenuiviruses into mammalian cells involves diverse pinocytic pathways and hundreds of cellular factors. The figure shows an overview of the different cellular locations of phenuivirus penetration. The entry pathways of RVFV, UUKV, and DABV appear in blue, red, and green, respectively. Sizes refer to nonvirus cargo that are typically sorted into the clathrin-mediated endocytosis, caveolin-mediated pathway, and macropinocytosis [75]. In the middle, the scales indicate the time taken by a nonvirus cargo to go from the plasma membrane to an endosomal compartment and the corresponding endosomal pH values [75]. DABV, Dabie virus; EEA1, early endosome antigen 1; LAMP1, lysosome-associated membrane protein 1; Rab5 and Rab7, Ras-related protein 5 and 7; RVFV, Rift Valley fever virus; UUKV, Uukuniemi virus.