Biochemical and Biophysical Research Communications
Antagonism of type I interferon by flaviviruses
Introduction
“It takes all the running you can do, to keep in the same place” – Through the looking Glass, by Lewis Carroll.
Leigh Van Valen, the founder of the “Red Queen Hypothesis”, used the Red Queen as a metaphor of the evolutionary arms races that are common to several genetic conflicts including host-pathogen interactions [1]. As a consequence of the selection pressure, throughout evolution eukaryotes developed sophisticated mechanisms to recognize and contain viral infections, and viruses in turn adapted multiple tricks to disrupt host defense pathways and hijack host processes to their advantage [2], [3], [4].
Type I interferons (IFNs) are a family of cytokines with essential roles in the defense of mammalian cells against viral infection and in the activation of immune responses. IFN was originally discovered more than 50 years ago by Isaacs and Lindenmann as a soluble factor produced by influenza virus-infected cells, and able to suppress subsequent infection with homologous or heterologous viruses in vitro [5], [6], [7]. Since then, remarkable advances have been made in our understanding of how type I IFN is produced in response to different stimuli, and how IFN signaling reprograms cellular biology to establish an effective antiviral role, and to enhance adaptive immune responses. In addition, several viral innate immune evasion strategies have been uncovered, which highlights the importance of the IFN signaling pathway in controlling viral replication and pathogenesis. This is of particular importance, since a better understanding of the molecular mechanisms by which different viruses manipulate and subvert the host immune response may contribute to the development of new live attenuated vaccines and antiviral drugs.
Flaviviruses are arthropod-borne viruses with a global impact on public health. They include important human pathogens such as Dengue (DENV), Japanese encephalitis (JEV), West Nile (WNV), Yellow Fever (YFV), Zika (ZIKV), and Tick-borne encephalitis (TBEV) viruses, many of which are resurging and spreading to new environments [8], [9]. Typically, these viruses contain a 10–11 kb positive-sense, single-stranded RNA genome that encodes a single polyprotein. After translation, the viral polyprotein localizes at the endoplasmic reticulum (ER) membrane where it is cleaved by viral and host proteases to generate three structural (C, prM and E), and seven non-structural (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) proteins. The structural proteins form the virion and are involved in viral attachment, fusion, and assembly. The non-structural proteins regulate viral transcription and replication and are required to modulate host antiviral responses. Interestingly, like all studied positive-strand RNA viruses, flaviviruses hijack cytoplasmic membranes in order to build functional sites for protein translation, processing and RNA replication [10], [11], [12], [13], [14], [15]. These sites, generally defined as replication compartments (RCs), are required to efficiently coordinate different steps of the viral life cycle and to shield replicating RNA from innate immunity surveillance [16], [17].
In this review, we provide an overview of the different strategies used by human pathogenic flaviviruses to antagonize type I IFN responses in order to establish a productive infection. We discuss both the passive and active mechanisms exploited by flaviviruses to prevent innate immune recognition by cytoplasmic pattern recognition receptors (PRRs) and subsequent IFN induction. In this regard, a particular focus is given to the recently described mechanisms of inhibition of the RIG-I like receptors (RLRs) and cyclic GMP-AMP (cGAS) - stimulator of the interferon gene protein (STING) pathways by DENV. In addition, we summarize several studies that, in the last 10 years, have contributed elucidating the mechanisms by which different flaviviruses impair the type I IFN signaling pathway.
Section snippets
Innate immune sensing of flaviviruses
As suggested by Isaacs and Lindenmann's seminal studies, today we know that type I IFN is produced by infected cells upon sensing of conserved “non-self” signatures, also known as pathogen-associated molecular patterns (PAMPs), by specific host PRRs (reviewed in Refs. [18], [19], [20], [21]).
Depending on their subcellular localization, PRRs can be classified in two main categories. The first category includes the membrane bound Toll-like receptors (TLRs), TLR3, TLR7, TLR8 and TLR9, that are
Antagonism of type I IFN production
As eukaryotic cells have evolved several mechanisms to distinguish self from non-self nucleic acids, flaviviruses, like many other viruses, have developed different strategies to escape, or at least delay, innate immune recognition. Indeed, flaviviruses have been shown to be either weak inducers of type I IFN [62], [63], [64], or late-in-infection inducers, allowing a replicative advantage to the virus during the early replication stages [31]. A summary of the strategies used by different
Antagonism of type I IFN signaling
As mentioned above, type I IFN plays an essential role for the control of viral infection. To date, several studies have shown that pretreatment with type I IFN can inhibit flavivirus replication in vitro, and it is important to control viral replication and spread in vivo. Specifically, mouse strains that are deficient in the type I IFN receptor, or in key components of the IFN signaling pathway such as STAT1 and STAT2, show enhanced lethality and viral replication upon infection with WNV [100]
Type I IFN as a determinant of host tropism
Mice are naturally resistant to infection with flaviviruses. However, as mentioned above, mouse strains that are deficient in key antiviral signaling pathways are highly susceptible to flavivirus infection. This restriction can be at least in part explained by the fact that many flaviviruses cannot efficiently block type I IFN induction and/or signaling in mice [36], [37], [103], [122]. In this regard, we and others have observed that while the DENV NS2B3 protease is able to bind and cleave
Summary and outlook
As summarized above, flaviviruses invest a big part of their genome to counteract both IFN induction and effector pathways, and establish a successful infection in humans. This emphasizes the importance of bypassing the early type I IFN response for effective viral replication. To date, the NS5 proteins of several flaviviruses have emerged as the most potent active antagonists of type I IFN signaling. However, the mechanisms of NS5 inhibition are different among flavivirus species, suggesting
Acknowledgements
We thank all past and present members of the Fernandez-Sesma and García-Sastre laboratories for their precious contribution to several of the studies discussed in this review. We apologize to all colleagues whose important work could not be cited due to space constraints. Current flavivirus research in the García-Sastre laboratory is supported by the NIH/NIAID grant U19AI118610. Flavivirus research in the Fernandez-Sesma laboratory discussed in this review has been supported by the NIH/NIAID
List of abbreviations
- 2′-O-MTase
- 2′-O-methyltransferase
- CARD
- caspase activation and recruitment domain
- cGAS
- cyclic GMP-AMP synthase
- cGMP-AMP
- cyclic-di-GMP-AMP
- DAMP
- danger associated molecular pattern
- DENV
- dengue virus
- dsRNAs
- double-stranded RNA
- ER
- endoplasmic reticulum
- gRNA
- genomic RNA
- IFIT
- interferon induced protein with tetratricopeptide repeats
- IFNAR
- interferon receptor
- IFNs
- type I interferons
- IkBα
- NFKB inhibitor alpha
- IKKε
- inhibitor of kappa-B kinase epsilon
- IRF3
- interferon regulatory factor 3
- IRF9
- interferon regulatory factor 9
- ISGF3
- ISG
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