Evasion of interferon responses by two hemorrhagic fever viruses

Adolfo García-Sastre

Mount Sinai School of Medicine, New York

Arthropod-borne viruses constitute important causative agents of emerging hemorrhagic fever diseases. 

We have been investigated how dengue virus (DENV), the most significant arbovirus pathogen in humans, and Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne virus of high lethality in humans, antagonize the type I IFN response.  DENV-infected cells are characterized by the degradation of STAT2, a transcription factor required for IFN signaling, resulting in inhibition of the type I IFN response. 

We found that the NS5 protein of dengue DENV, known to be the viral RNA-dependent RNA polymerase of this positive strand RNA virus, mediates STAT2 degradation after undergoing proteolytical maturation from the precursor viral polyprotein.  NS5-mediated degradation of STAT2 appears to be species-specific, as it readily occurs in human cells but not in mouse cells, and might contribute to the host tropism of DENV.

We have also indentified the presence of a protease motif associated with the amino-terminus of the L protein of CCHFV, also known to be the viral RNA-dependent RNA polymerase of this negative strand RNA virus, that removes ubiquitin and the IFN-induced ubiquitin-like molecule ISG15 from conjugated cellular substrates, inhibiting antiviral innate immune responses. The structure of this protease revealed the molecular reasons responsible for substrate specificity. 

Our experiments increase our understanding of viral evasion of innate immunity, help with the possible development of an improved DENV mouse model, and hopefully will lead to new classes of inhibitors for these two hemorrhagic fever viruses.