Human hemorrhagic Fever causing arenaviruses: molecular mechanisms contributing to virus virulence and disease pathogenesis

Abstract

Arenaviruses include multiple human pathogens ranging from the low-risk lymphocytic choriomeningitis virus (LCMV) to highly virulent hemorrhagic fever (HF) causing viruses such as Lassa (LASV), Junin (JUNV), Machupo (MACV), Lujo (LUJV), Sabia (SABV), Guanarito (GTOV), and Chapare (CHPV), for which there are limited preventative and therapeutic measures. Why some arenaviruses can cause virulent human infections while others cannot, even though they are isolated from the same rodent hosts, is an enigma. Recent studies have revealed several potential pathogenic mechanisms of arenaviruses, including factors that increase viral replication capacity and suppress host innate immunity, which leads to high viremia and generalized immune suppression as the hallmarks of severe and lethal arenaviral HF diseases. This review summarizes current knowledge of the roles of each of the four viral proteins and some known cellular factors in the pathogenesis of arenaviral HF as well as of some human primary cell-culture and animal models that lend themselves to studying arenavirus-induced HF disease pathogenesis. Knowledge gained from these studies can be applied towards the development of novel therapeutics and vaccines against these deadly human pathogens.

Keywords: Junin virus; Lassa virus; arenaviruses; immune evasion; pathogenic mechanisms; virus replication.

Figure 1

Arenavirus genome structure: Arenaviruses are enveloped RNA viruses with a single-stranded ambisense genome that is composed of two segments. The genomic L (large) segment encodes the Z matrix protein and the L polymerase protein, and the S (small) segment encodes the glycoprotein (GP) and nucleoprotein (NP). The genes encoded on each segment are separated by noncoding intergenic regions (IGR). The linear genomes are flanked by the conserved 5’ and 3’ untranslated regions (UTRs).

Figure 2

Arenaviral ambisense-genome replication strategy: due to the ambisense coding strategy of the arenaviruses, the NP (and L) genes are transcribed directly from the viral genomic segments into mRNAs, whereas the GP (and Z) mRNAs must be transcribed from the antigenomic strands after genome replication.

Figure 3

Arenavirus life cycle. 1. Cellular entry is mediated by different cellular receptors (αDG for OW and NW clade C arenaviruses; TfR1 for NW Clade B). Entry of some viruses (e.g., LASV) may also involve a pH-dependent switch to an intracellular receptor (LAMP1) located in the lysosomes. 2. Virus uptake into cells is mediated by endocytosis (OW arenaviruses: clathrin-independent, NW: clathrin-dependent). 3. Virus fusion occurs with the late endosome. 4. Viral RNP is released into the cytoplasm via a pH-dependent membrane fusion mechanism. 5. Viral genome replication, transcription, and protein expression strictly occur in the cytoplasm. 6. Virion assembly and budding occur at the plasma membrane.