A dead-end host: is there a way out? A position piece on the ebola virus outbreak by the international union of immunology societies.

Abstract

The fact that not everyone with Ebola virus disease (EVD) has died during the ongoing outbreak in West Africa, with an estimated case fatality rate of 70.8% by September 2014 (1), suggests that some kind of immunity to this virus is possible. If left unchecked, this scenario will undoubtedly shift to a higher figure, as health-care conditions in many of the countries affected may not always enable infected hosts to recover. Although gender differences in the survival, incidence, and/or severity of infection are unknown, the current Ebola virus outbreak represents an unprecedented disaster for humans (1, 2) and a zoonotic successful strategy (3) for a virus that cunningly and rapidly hijacks innate immunity to devastating effect. Human to human transmission is via contact with bodily fluids from symptomatic patients, which was identified in the first epidemic almost 40 years ago, but unlike prior epidemics, which consisted of sporadic short periods of human transmission, there is now a shift to a prolonged period of viral transmission (over 9 months at the time of writing). This is, in part, a reflection of the movement of people into urban densely populated regions (2). In fact, there are distinct parallels between the first outbreak in the Zaire with today’s outbreak – both being caused by Zaire Ebolavirus (1, 4). Importantly, however, the current and ongoing outbreak is occurring in this region for the first time, and there are fears that without blocking transmission, Ebola may become endemic (2). What then are the medical efforts under way to halt the spread of Ebola with immune therapies and vaccine strategies? Should we temper the usual scientific rigor of clinical trials and roll-out candidate vaccines and therapies directly into people? How should the scientific, and specifically the immunology community, meet the rapidity of EVD spread, which without doubt is the major challenge and crisis of today. Ebola, a filovirus, encodes seven genes: nucleoprotein (NP), VP35 (polymerase co-factor), VP40 (matrix protein), glycoprotein (GP), VP30 (transcription activator), VP24 (secondary matrix protein), and RNA-dependent RNA polymerase (5). The most likely routes of Ebola entry into the body are via mucosal surfaces, the conjunctiva, the oropharynx, or injured skin routes (6). From human and monkey studies, the primary targets are dendritic cells, monocytes, macrophages, and Kupffer cells in the liver and entry mechanisms include the GP interacting with an unidentified receptor and inducing: (i) endocytosis mediated by lipid rafts; (ii) macropinocytosis; and (iii) clathrin-mediated transport (5). Experimental models have shown that virus-like particles (VLPs) composed of GP and VP40 activate endothelial cells that upregulate expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin, which jointly results in an increase in endothelial permeability (7). It is also likely that the increase in pro-inflammatory cytokines, shown experimentally and in plasma samples from patients with Ebola infection (5), contribute to enhancing vasodilation and the resulting cytokine storm (8) causes immune dysfunction and general “shut-down” of all immunity. Additionally, monkey models have shown that Ebola infection causes apoptosis in by-stander CD4 and CD8 lymphocytes and NK cells (9). These devastating effects result in the clinical symptoms of hemorrhagic lesions in the skin, mucous membranes, visceral organs, and large effusions in body cavities. There is also multifocal necrosis most predominantly in the liver, spleen, kidneys, testes, and ovaries (5). As with all pathogens, Ebola has evolved to evade innate immunity by hijacking specific anti-viral pathways, resulting in immunosuppression. VP35 and VP24 inhibit type I interferon activity. VP35 inhibits induction of IFN-beta production by suppressing phosphorylation and dimerization of IFN regulatory factor 3 (IRF-3) and enhancing SUMOylation of IRF-7 (5, 10). Viral P24 inhibits type I and type II IFN signaling by inhibiting nuclear signaling transducer ad activator of transcription 1 (STAT 1) (10). The combined effect of these immune evasion strategies along with eliciting acute immune activation, inflammation, and a cytokine storm is lethal for the host and, as this current epidemic has shown, more than two-thirds of infected people with EVD will die. Are there clues from individuals who have survived EVD or properties of the virus that can be exploited to develop vaccine candidates?