Distinct Molecular Mechanisms of Host Immune Response Modulation by Arenavirus NP and Z Proteins

Abstract

Endemic to West Africa and South America, mammalian arenaviruses can cross the species barrier from their natural rodent hosts to humans, resulting in illnesses ranging from mild flu-like syndromes to severe and fatal haemorrhagic zoonoses. The increased frequency of outbreaks and associated high fatality rates of the most prevalent arenavirus, Lassa, in West African countries, highlights the significant risk to public health and to the socio-economic development of affected countries. The devastating impact of these viruses is further exacerbated by the lack of approved vaccines and effective treatments. Differential immune responses to arenavirus infections that can lead to either clearance or rapid, widespread and uncontrolled viral dissemination are modulated by the arenavirus multifunctional proteins, NP and Z. These two proteins control the antiviral response to infection by targeting multiple cellular pathways; and thus, represent attractive targets for antiviral development to counteract infection. The interplay between the host immune responses and viral replication is a key determinant of virus pathogenicity and disease outcome. In this review, we examine the current understanding of host immune defenses against arenavirus infections and summarise the host protein interactions of NP and Z and the mechanisms that govern immune evasion strategies.

The Role of the Host Ubiquitin System in Promoting Replication of Emergent Viruses

“…This virus encodes four proteins: nucleoprotein (NP), surface glycoprotein precursor (GPC), L polymerase and RING finger protein Z. The Z protein plays an important role in viral assembly by assisting in the integration of GP, NP and polymerase L in viral progeny [51]. Z protein interaction with the ITCH E3 ligase was required for LASV replication.…”

Inhibition of Arenavirus Entry and Replication by the Cell-Intrinsic Restriction Factor ZMPSTE24 Is Enhanced by IFITM Antiviral Activity

“…Several intrinsic immune factors, also known as restriction factors, inhibit the infection of diverse enveloped viruses (Chemudupati et al, 2019;Stott et al, 2020). Amongst these factors are the human interferon-induced transmembrane protein (IFITM) family and the zinc metalloprotease, ZMPSTE24.…”

“…To date, there is limited information about how arenavirus infections may be antagonised by cell intrinsic factors (Radoshitzky et al, 2010;Chen et al, 2019;Stott et al, 2020), and the putative role of ZMPSTE24 in arenavirus biology has not yet been explored. In this study, we examined whether ZMPSTE24 is involved in arenavirus entry restriction.…”

Inhibition of arenavirus entry and replication by the cell-intrinsic restriction factor ZMPSTE24 is enhanced by IFITM antiviral activity

“…Several restriction factors potently inhibit the infection of diverse enveloped viruses (31,32). Amongst these factors are the interferon-induced transmembrane proteins (IFITMs) and the zinc metalloprotease, ZMPSTE24 (33,34).…”

“…To date, there is limited information about how arenavirus infections may be antagonised by host restriction factors (32,46,47), and also the putative role of ZMPSTE24 in arenavirus biology has not yet been explored. Given that ZMPSTE24 is an important innate defence factor against a number of pathogenic viruses, it is conceivable that ZMPSTE24 may affect the viral endocytic entry process of arenaviruses.…”