Stimulation of Ebola virus production from persistent infection through activation of the Ras/MAPK pathway

Abstract

Human infections with Ebola virus (EBOV) result in a deadly viral disease known as Ebola hemorrhagic fever. Up to 90% of infected patients die, and there is no available treatment or vaccine. The sporadic human outbreaks are believed to result when EBOV ''jumps'' from an infected animal to a person and is subsequently transmitted between persons by direct contact with infected blood or body fluids. This study was undertaken to investigate the mechanism by which EBOV can persistently infect and then escape from model cell and animal reservoir systems. We report a model system in which infection of mouse and bat cell lines with EBOV leads to persistence, which can be broken with low levels of lipopolysaccharide or phorbol-12-myristate-13-acetate (PMA). This reactivation depends on the Ras/MAPK pathway through inhibition of RNA-dependent protein kinase and eukaryotic initiation factor 2␣ phosphorylation and occurs at the level of protein synthesis. EBOV also can be evoked from mice 7 days after infection by PMA treatment, indicating that a similar mechanism occurs in vivo. Our findings suggest that EBOV may persist in nature through subclinical infection of a reservoir species, such as bats, and that appropriate physiological stimulation may result in increased replication and transmission to new hosts. Identification of a presumptive mechanism responsible for EBOV emergence from its reservoir underscores the ''hit-and-run'' nature of the initiation of human and/or nonhuman primate EBOV outbreaks and may provide insight into possible countermeasures to interfere with transmission.

Reciprocal Regulation of AKT and MAP Kinase Dictates Virus-Host Cell Fusion

“…12). These observations imply that paramyxovirus-resistant host cells have an elevated pAKT level but less ERK activation and that differential Ras activation modulates the permissibility to viral fusion (16,17,49). Thus, our observations establish a new framework for redefining the host cell susceptibility or resistance to a given virus and thereby reveal a novel therapeutic strategy.…”

Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance

“…In susceptible mice relative to resistant mice, genes associated with EBOV infection were differentially induced. Early in infection in the spleens of susceptible mice at day 1 p.i., we observed enrichment of p38 MAPK and ERK signaling, processes that stimulate productive EBOV infection (16, 17). Additionally we observed increased NFkB expression and induction of proinflammatory processes, which may reflect early targets of infection in the secondary lymphoid organs.…”

Interaction between Ebola Virus Glycoprotein and Host Toll-Like Receptor 4 Leads to Induction of Proinflammatory Cytokines and SOCS1

“…5). Strong et al recently reported that LPS stimulation of cells persistently infected with Ebola virus led to enhanced production of virus (28). It is tempting to speculate that TLR4 triggering by LPS leads to the induction of ubiquitin ligases such as SOCS1 and TRAF6, which may then promote VLP budding due in part to their ubiquitination activity.…”