Molecular mechanisms of Ebola pathogenesis

Abstract

Ebola viruses (EBOVs) and Marburg viruses (MARVs) are among the deadliest human viruses, as highlighted by the recent and widespread Ebola virus outbreak in West Africa, which was the largest and longest epidemic of Ebola virus disease (EVD) in history, resulting in significant loss of life and disruptions across multiple continents. Although the number of cases has nearly reached its nadir, a recent cluster of 5 cases in Guinea on March 17, 2016, has extended the enhanced surveillance period to June 15, 2016. New, enhanced 90-d surveillance windows replaced the 42-d surveillance window to ensure the rapid detection of new cases that may arise from a missed transmission chain, reintroduction from an animal reservoir, or more important, reemergence of the virus that has persisted in an EVD survivor. In this review, we summarize our current understanding of EBOV pathogenesis, describe vaccine and therapeutic candidates in clinical trials, and discuss mechanisms of viral persistence and long-term health sequelae for EVD survivors.

Keywords: Ebola survivors; Ebola vaccines; antivirals; immunoevasion; viral hemorrhagic fever.

Figure 1

Ebola virus life cycle. (1) EBOV gains cell entry by receptor‐mediated endocytosis. (2) Acidification of the endocytic vesicle, followed by fusion of the virus and host membranes, releases the EBOV nucleocapsid into the cytoplasm. (3) The RNA‐dependent RNA polymerase transcribes individual mRNA from the negative‐sense genome in a 3′ to 5′ direction. Each mRNA is capped at the 5′ end and contains a poly‐A tail. (4) During replication, the promoter at the 3′ end of the genomic RNA drives synthesis of the full‐length, positive‐sense, antigenomic RNA, which, in turn, serves as a template for the production of progeny, negative‐sense genomes. (5) Nucleocapsid proteins (VP35, L, VP30, and NP) associate with negative‐sense genome progeny, whereas (6) GP and sGP are further modified in the endoplasmic reticulum and Golgi body. (7) When sufficient levels of the negative‐sense genomes and viral proteins are reached, they are assembled at the plasma membrane with membrane‐associated proteins (matrix proteins VP24 and VP40 and GP). (8) Complete virions bud from the cell surface.

Figure 2

Ebola virus pathogenesis. Ebola virus initially and preferentially infects monocytes, macrophages, and DCs. Infection of DCs impairs their maturation and suppresses type I IFN responses, thereby preventing T cell activation. Infection of monocytes and macrophages leads to the robust expression of inflammatory mediators. Secreted chemokines can recruit more monocytes, which act as new targets for viral infection. Inflammatory mediators, reactive oxygen species, and nitric oxide can induce apoptosis leading to lymphocyte death. The lack of lymphocytes, such as CD4 T cells, inhibits the ability of the virus to induce an Ab response. Production of EBOV secreted glycoprotein (sGP) usurps any GP‐specific Abs that are made. Eventually, the inflammatory cytokines are responsible for vascular leakage. EBOV systemically disseminates to liver, kidneys, adrenal glands, and endothelial cells, which contributes to symptoms associated with hemorrhagic fever.

Figure 3

EBOV evades type I IFN responses. EBOV can prevent production of and cellular responses to type I IFN. In vitro studies have shown that EBOV VP35 can block RLR signaling by binding to dsRNA or binding PACT, preventing production of IFN‐α/β. VP35 can interact with host SUMOylation machinery, including SUMO E2 enzyme Ubc9 and E3 ligase PIAS1, to promote the degradation of IRF7/IRF3. VP35 can also prevent the phosphorylation of IRF3 by IKKɛ. EBOV VP24 can prevent cellular responses to IFN‐α/β by binding to the nuclear importer protein karyopherin α‐1 (KPNα1), preventing it from binding to phosphorylated STAT1, thus limiting the accumulation of nuclear STAT1 and preventing IFN‐induced gene expression. ISRE, IFN‐stimulated response element.

Figure 4

Long‐term post‐EBOV consequences. EBOV entry and persistence into organs that are immune privileged, including the ear, testis, eye, CNS, pregnant uterus, and muscle tissue, have been observed in clinically recovered patients, resulting in Ebola disease sequelae.