Lassa virus protein-protein interactions as mediators of Lassa fever pathogenesis

Abstract

Viral hemorrhagic Lassa fever (LF), caused by Lassa virus (LASV), is a significant public health concern endemic in West Africa with high morbidity and mortality rates, limited treatment options, and potential for international spread. Despite advances in interrogating its epidemiology and clinical manifestations, the molecular mechanisms driving pathogenesis of LASV and other arenaviruses remain incompletely understood. This review synthesizes current knowledge regarding the role of LASV host-virus interactions in mediating the pathogenesis of LF, with emphasis on interactions between viral and host proteins. Through investigation of these critical protein-protein interactions, we identify potential therapeutic targets and discuss their implications for development of medical countermeasures including antiviral drugs. This review provides an update in recent literature of significant LASV host-virus interactions important in informing the development of targeted therapies and improving clinical outcomes for LF patients. Knowledge gaps are highlighted as opportunities for future research efforts that would advance the field of LASV and arenavirus pathogenesis.

Keywords: Arenavirus; Emerging RNA virus; Hemorrhagic fever virus; Host-virus interactions; Lassa fever pathogenesis; Lassa virus; Protein–protein interactions.

Fig. 1

Arenavirus structure and genome organization. A Arenaviruses are 90–110 nm in diameter and have a host-derived lipid envelope expressing glycoprotein complex (GPC) spikes containing glycoprotein 1 (GP1), glycoprotein 2 (GP2), and stable signal peptide (SSP) on the surface. Inside the membrane is a layer containing the zinc finger matrix protein (Z) and viral RNA encapsulated by nucleoprotein (NP). NP with the viral RNA acts as a scaffold for the ribonucleoprotein complex involving the L protein RNA-dependent RNA polymerase (RdRP). Viral RNA is split into two species, a large and small RNA. B Arenavirus ambisense RNA encodes for four proteins. The large RNA encodes for Z and L, while the small RNA encodes for GPC and NP. Both segments are flanked by 5’ and 3’ untranslated regions (UTRs) and have structurally distinct intergenic regions (IGRs) which are important in terminating transcription

Fig. 2

Overview of protein interactions during the LASV arenavirus life cycle in the host cell. 1 GP1 present on the viral surface binds α-dystroglycan for primary attachment. Receptors AXL, Tyro3, DC-SIGN, and LSECtin are also involved in interanalizing the LASV virion. Glycosylation of GP1 hinders neutralizing antibody binding. 2 pH-dependent GP1 binding to LAMP1 in the late endosome precedes GP2-mediated fusion. GP2 causes fusion at the endosomal membrane and deposition of viral contents into the host cytoplasm. 3 Once in the cytoplasm, RNP comprised of L protein (RdRP), NP, and vRNA initiate transcription and replication of the viral genome. Replication effiency correlates well to pathogenicity. 4 Viral transcriptional and translational products include NP, L protein, Z, and the GP1-GP2 precursor. 5 Viral proteins interfere with the host antiviral response and aid in immune evasion and supression. NP degrades dsRNA, preventing RIG-I and MDA5 recognition. 5’ and 3’ UTRs form panhandle structures with single nucleotide mismatches, inhibiting RIG-I and MDA5. Z inhibits RIG-I and MAVS association. NP also modulates IKKε and DDX3 activity, preventing establishment of an antiviral state in the host cell. NP has decoy caspace cleavage sites which decrease apoptosis. 6 GPC maturation from the GP1-GP2 precursors and transport occur in the endoplasmic reticulum and Golgi apparatus. SSP is co-translationally cleaved from GPC, and SKI-1/S1P processes GPC for maturation and formation of virions and fusions. 7 Virions assemble at the surface of the host cell and bud off from the plasma membrane with a host-derived lipid envelope. Z late domains PTAP and PPPY interact with ESCRT-1 and NEDD4 to mediate multivesicular budding

Fig. 3

Features and domains of the LASV genes. A RING-finger matrix protein Z has a myristylation site at glycine 2, a zinc finger domain in the middle, and PTAP and PPXY motifs at the C-terminus. B RNA-dependent RNA polymerase (RdRP) L has a cap-snatching endonuclease at the N-terminus and an RdRP catalytic domain. C Nucleoprotein NP consists of a multimeraization domain at the N-terminus and an exonuclease domain at the C-terminus. D Glycoprotein GP is divided into SSP, GP1, and GP2 with accompanying cleavage sites