Evasion of the Interferon-Mediated Antiviral Response by Filoviruses

Washington B Cárdenas

doi:10.3390/v2010262

Abstract

The members of the filoviruses are recognized as some of the most lethal viruses affecting human and non-human primates. The only two genera of the Filoviridae family, Marburg virus (MARV) and Ebola virus (EBOV), comprise the main etiologic agents of severe hemorrhagic fever outbreaks in central Africa, with case fatality rates ranging from 25 to 90%. Fatal outcomes have been associated with a late and dysregulated immune response to infection, very likely due to the virus targeting key host immune cells, such as macrophages and dendritic cells (DCs) that are necessary to mediate effective innate and adaptive immune responses. Despite major progress in the development of vaccine candidates for filovirus infections, a licensed vaccine or therapy for human use is still not available. During the last ten years, important progress has been made in understanding the molecular mechanisms of filovirus pathogenesis. Several lines of evidence implicate the impairment of the host interferon (IFN) antiviral innate immune response by MARV or EBOV as an important determinant of virulence. In vitro and in vivo experimental infections with recombinant Zaire Ebola virus (ZEBOV), the best characterized filovirus, demonstrated that the viral protein VP35 plays a key role in inhibiting the production of IFN-α/β. Further, the action of VP35 is synergized by the inhibition of cellular responses to IFN-α/β by the minor matrix viral protein VP24. The dual action of these viral proteins may contribute to an efficient initial virus replication and dissemination in the host. Noticeably, the analogous function of these viral proteins in MARV has not been reported. Because the IFN response is a major component of the innate immune response to virus infection, this chapter reviews recent findings on the molecular mechanisms of IFN-mediated antiviral evasion by filovirus infection.

Highlights

Introduction to FilovirusThe filoviruses are members of the Mononegavirales with a non-segmented, negative-sense, single stranded RNA genome [1]
CD28, CD40L, CTLA4, Fas, FasL, and perforin [43,44,45,54]. This chain of immunological events is likely disrupted in fatal cases of filovirus hemorrhagic fever (HF) by Marburg virus (MARV) and Ebola virus (EBOV) targeting host dendritic cells, which are key antigen presenting cells (APC) that modulate innate and adaptive immune responses [55,56,57]
U373 cells was able to block reporter gene activation induced by LPS (Figure 3). It is unclear what benefit EBOV gains by inhibiting the TRIF/TRAM arm of TLR4 signaling, but we can speculate that activation of signaling through TLR4 by EBOV GP can induce the production of proinflammatory cytokines and chemokines that contribute to Ebola HF (EHF) pathogenesis [118]

Summary

Introduction to Filovirus

The filoviruses are members of the Mononegavirales with a non-segmented, negative-sense, single stranded RNA genome [1]. The second filovirus infection, but the first in a natural setting, was reported almost 10 years later in two nearly simultaneous outbreaks in southern Sudan and Zaire (the present Democratic Republic of Congo, DRC) These outbreaks led to the discovery of the second genus of the Filoviridae family, EBOV, and the two new species of the genus, Sudan Ebola virus (SEBOV) and ZEBOV, respectively [4,5]. The third species of EBOV was identified during another inadvertent importation of infected macaques from the Philippines into a quarantine facility in Reston, Virginia, USA, in 1989 [23] This novel virus, named Reston Ebola virus (REBOV), was able to infect humans, as assessed by serology, but without apparent severe illness. Reports of a developing outbreak of HF in western Uganda, Bundibugyo district, in November 2007, lead to the identification of the fifth EBOV species, Bundibugyo Ebola virus (BEBOV) [31]. These findings complicate the picture regarding the role that pigs may have in the chain of transmission of filovirus to human and non-human primates

Filovirus pathogenesis

Evasion of interferon response by Filovirus

Conclusions