Date Published: September 11, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Girish J. Kotwal, Steven Hatch, William L. Marshall.
The innate immune response is initiated by the interaction of stereotypical pathogen components with genetically conserved receptors for extracytosolic pathogen-associated molecular patterns (PAMPs) or intracytosolic nucleic acids. In multicellular organisms, this interaction typically clusters signal transduction molecules and leads to their activations, thereby initiating signals that activate innate immune effector mechanisms to protect the host. In some cases programmed cell death—a fundamental form of innate immunity—is initiated in response to genotoxic or biochemical stress that is associated with viral infection. In this paper we will summarize innate immune mechanisms that are relevant to viral pathogenesis and outline the continuing evolution of viral mechanisms that suppress the innate immunity in mammalian hosts. These mechanisms of viral innate immune evasion provide significant insight into the pathways of the antiviral innate immune response of many organisms. Examples of relevant mammalian innate immune defenses host defenses include signaling to interferon and cytokine response pathways as well as signaling to the inflammasome. Understanding which viral innate immune evasion mechanisms are linked to pathogenesis may translate into therapies and vaccines that are truly effective in eliminating the morbidity and mortality associated with viral infections in individuals.
The innate immune system is as ancient as the bacterial immune response to bacteriophages. As the nature and complexity of viral innate immune evasion mechanisms evolved, so has the innate—and eventually adaptive—immune response to these mechanisms. The innate immune response in mammals is initiated by the interaction of stereotypical pathogen components with germ-line encoded receptors. In some cases, signal transduction pathways are stimulated in sentinel cells, such as macrophages and dendritic cells. Stimulation of these signaling pathways promptly activates innate effector mechanisms to protect the host; these innate immune signals also activate antigen-presenting cells that are critical to the eventual adaptive immune response of the host . In this paper we will summarize findings in the innate immune system that are relevant to viral pathogenesis and outline the evolution of viral mechanisms that suppress innate immunity in mammalian hosts.
The receptors of the innate immune system are germ-line encoded and include the nucleotide-binding domain leucine-rich repeat containing receptors, the Toll-like receptors (TLRs), and the RIG-I-like receptors (RLRs). The RLRs are cytosolic sensors of pathogen RNA and include proteins encoded by the retinoic acid-inducible gene-I (RIG-I) , the melanoma differentiation-associated gene 5 (MDA5) [3, 4], and the laboratory of genetics protein 2 (LGP2)  and DDX3, which is thought to associate with RIG-I . The helicase domains of RLRs detect the cytosolic RNA of microbial pathogens, generating signals that drive production of cytokines and interferons. Helicases are ATP-dependent enzymes that unidirectionally translocate along a transcript thereby dissociating nucleic acid duplexes . The RIG-I and MDA5 RLRs play critical roles in the recognition of foreign RNA and in the response to many viral pathogens. MDA5 and RIG-I contain a DExD/H-box RNA helicase domain and caspase activation and recruitment domains (CARDs). RIG-I recognizes 5′-triphosphate RNA, and MDA5 can recognize complex webs of pathogen RNA, comprised of both viral single-stranded and double-stranded RNA . The LGP2 RLR protein was found to lack a CARD domain and was originally identified as a dominant negative inhibitor of RIG-I signaling . Under some circumstances, though, it appears LGP2 can stimulate RLRs such as MDA5 and RIG-I . CARD engagement leads to interaction with a protein known as mitochondrial antiviral signaling protein (MAVS) that is alternatively designated CARDIF, HELICARD, or IPS-1 (referred to here as MAVS) [9, 10]. Subsequently, upon oligomerization, MAVS signals to members of the IKK family of kinases that are critical for the innate immune response . Thus MAVS induces IKKα and IKKβ stimulation that leads to translocation of NF-κB, as well as IKKε/TBK1 stimulation that leads to translocation of IRF-3. These transcription factors stimulate production of cytokines, other innate immune response proteins, and type I interferons .
Prokaryotic organisms encode primordial proteins that recognize the molecular patterns (e.g., specific sequences of DNA of bacteriophages) from pathogens (i.e., bacteriophages) and thus can be considered to possess a primitive innate immune system. Although the mechanisms of innate immunity in bacteria differ radically from those of higher organism, four principles of innate immunity are preserved in several mechanisms (Table 1). First, the clustered regularly space short palindromic repeats (CRISPERs) of bacteria and archaea encode a series of palindromic sequences that target pathogen DNA and suppress their transcription in a way similar to the antiviral action of microRNAs of Drosophila [58, 59]. Second, following exposure of prokaryotes to bacteriophages, the phage shock protein (Psp) signaling pathway involves an unknown sensor and signal transduction by the leucine zipper protein PspB. PsP signaling is initiated in response to loss of cell membrane integrity induced by stresses such a bacteriophage infection . This is similar in principle to the enhanced cell membrane integrity mediated by interferon in the mammalian antiviral response [2, 13, 19]. A third conserved principle is intracytosolic nucleic acid recognition (analogous to mammalian RLRs or Drosophila DICER) that triggers an innate immune response. In bacteria, restriction endonucleases recognize and digest bacteriophage nucleic acids, while specificity of this response is maintained by bacterial methylation of its native DNA. Fourth, programmed death of bacteriophage-infected bacteria induced by the MazF protein can pre-empt spread of viral infection, as is true of proapoptotic proteins in higher organisms (reviewed in ). Bacteriophage mechanisms to evade the bacterial innate immune pathways include rapid mutation to generate DNA sequence diversity that evades CRISPER, acquisition of host bacterial methylases to mask restriction sites in bacteriophage DNA , and programmed cell death resistance . A bacteriophage mechanism to evade PsP signaling has not been reported, although it is tempting to speculate that the rapid mutation observed during bacteriophage infection might avoid detection by the Psp pathway. Although the details and evolution of innate immune mechanisms in bacterial cells are highly divergent from multicellular organisms (Table 1), the principal functional attributes of innate immune recognition and viral evasion are remarkably conserved, especially in the invertebrate innate immune responses.
Many viral mechanisms have evolved to evade the immune response. Surprisingly, the general outline of innate antiviral mechanism is remarkably persistent throughout evolution, such as DNA restriction/dicing and programmed cell death; however, differences between innate immune responses of distinct organisms are often more striking and may hint at novel innate immune evasion pathways still undiscovered in mammalian virus-host interactions. Signaling to interferon resembles antiviral protein induction in Drosophila and in some respects, even in bacteria. The evolutionary conservation of these mechanisms suggests their study will advance understanding of viral pathogenesis and that these pathways would be worthy targets of antiviral inhibitors.