Antiviral Defense and Innate Immune Memory in the Oyster

Abstract

The Pacific oyster, Crassostrea gigas, is becoming a valuable model for investigating antiviral defense in the Lophotrochozoa superphylum. In the past five years, improvements to laboratory-based experimental infection protocols using Ostreid herpesvirus I (OsHV-1) from naturally infected C. gigas combined with next-generation sequencing techniques has revealed that oysters have a complex antiviral response involving the activation of all major innate immune pathways. Experimental evidence indicates C. gigas utilizes an interferon-like response to limit OsHV-1 replication and spread. Oysters injected with a viral mimic (polyI:C) develop resistance to OsHV-1. Improved survival following polyI:C injection was found later in life (within-generational immune priming) and in the next generation (multi-generational immune priming). These studies indicate that the oyster's antiviral defense system exhibits a form of innate immune-memory. An important priority is to identify the molecular mechanisms responsible for this phenomenon. This knowledge will motivate the development of practical and cost-effective treatments for improving oyster health in aquaculture.

Keywords: Crassostrea; OsHV-1; RNAi; immune priming; interferon.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Conceptual diagram of the interferon-like antiviral response of Crassostrea gigas involving the TLR/NF-κB, RIG-1/MAVS, and putative cGAS/STING signaling pathways that result in the transcription of antiviral genes. The oyster genome encodes several novel toll-like receptors (TLRs) that lack transmembrane domains, implying they have a cytoplasmic function. These novel TLRs and downstream signaling adaptors are upregulated in response to OsHV-1 inoculation [34,36,52]. The oyster has a functional RIG-1 pathway that senses the presence of cytoplasmic dsRNA (i.e., polyI:C) and signals via downstream MAVS and TRAF adaptors [46]. The transcription factor IRF appears to function downstream of oyster MAVS and activates the IFN promoter and IFN stimulated response elements (ISRE) in mammalian cells [46,53]. Activation of IRF and NF-κB results in their translocation to the cell nucleus, leading to the transcription of antiviral genes. It is not currently known if oysters have a functional cGAS/STING-dependent antiviral response (pathway highlighted with grey arrows) [54]. The oyster genome encodes a STING homologue with three N-terminal transmembrane domains followed by a STING domain [10]. Oyster STING binds cyclic dinucleotides (CDNs) [55] and interacts with downstream TBK1 kinase [39]. Functional assays are required to determine if oyster cGAS binds cytosolic DNA and synthesizes CDNs. Note the unusual protein domains for RIG-like receptors and STING. Novel RIG-like receptors contain N-terminal death domains and novel STING either lack transmembrane domains or contain TIR domains [56]. TIR domain-containing proteins such as TLRs and interleukin-1 receptors are known to play key roles in innate immune signaling [57]. TLR, toll-like receptor; MyD88, myeloid differentiation primary response 88; IRAK, interleukin receptor-associated kinase; TRAF, TNF-receptor associated factor; IKK, IκB kinase; IκB, Inhibitor of κB; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; RIG-1, retinoic acid-inducible gene-1-like receptor; MAVS, mitochondria antiviral signaling protein; IFN, interferon; IRF, interferon regulatory factor; cGAS, cyclic GMP-AMP synthase; STING, stimulator of IFN genes; TBK1, tank binding kinase 1; STAT, signal transducer and activator of transcription; SOCS, suppressor of cytokine signaling; ISRE, IFN stimulated response element.