Trends in Immunology
Volume 38, Issue 1, January 2017, Pages 53-65
Journal home page for Trends in Immunology

Review
Sequence-Specific Sensing of Nucleic Acids

https://doi.org/10.1016/j.it.2016.10.006Get rights and content

Trends

Computational analyses of host and pathogen genomes led to the identification of unique immunostimulatory sequence patterns. In parallel, structural and biochemical analyses of innate receptors confirmed the existence of specificity for unique sequence motifs.

Large-scale recoding of viral genomes uncovers new interactions between the innate immune system and sequence patterns found in viral genomes.

The sequence of nucleic acids modulates their structure, stability, and direct recognition by cellular pattern recognition receptors.

Endogenous sequences of foreign origins that are normally silenced can induce innate responses through nucleic acid-sensing pathways.

Better characterization of the innate pathways responsible for sensing foreign sequences will improve computational detection and bring critical insights for gene therapy and vaccine design.

Innate immune cells are endowed with many nucleic acid receptors, but the role of sequence in the detection of foreign organisms remains unclear. Can sequence patterns influence recognition? In addition, how can we infer those patterns from sequence data? Here, we detail recent computational and experimental evidence associated with sequence-specific sensing. We review the mechanisms underlying the detection and discrimination of foreign sequences from self. We also describe quantitative approaches used to infer the stimulatory capacity of a given pathogen nucleic acid species, and the influence of sequence-specific sensing on host–pathogen coevolution, including endogenous sequences of foreign origin. Finally, we speculate how further studies of sequence-specific sensing will be useful to improve vaccine design, gene therapy and cancer treatment.

Section snippets

Microbial-Specific Sequence Motifs Are a Class of Pathogen-Associated Molecular Pattern

The innate immune system detects the presence of foreign organisms and initiates a coordinated response to eliminate infectious threats. Among the microbial products sensed by innate immune effectors, efficient recognition of nucleic acids (DNA and RNA) is critical, as suggested by the existence of several families of receptors specific to these ligands (Table 1). However, the detection of nucleic acids also presents a risk for self-recognition, and self-activation in response to host nucleic

Computational Approaches to Define a Foreign Sequence

The earliest computational approaches to defining a foreign sequence used motif usage as a self versus non-self discriminant. A pioneering study showed that a metric based on dinucleotide usage could adequately discriminate a random contiguous segment of human DNA from a random contiguous segment of bacterial DNA [3]. The primary dinucleotide that enforces this discrimination is CpG. Indeed, CpG methylation of DNA, a feature vastly more prevalent in mammals than in bacteria, promotes cytosine

Microbial Avoidance of Sequence Patterns Suggests Immunostimulatory Properties

The first demonstration of sequence-specific immune sensing of foreign nucleic acids came from the discovery that CpG motifs in bacterial DNA trigger B cell activation [4]. The same immunostimulatory potential of certain dinucleotides was suggested by genomic analyses that identified a pervasive suppression of CpG and UpA dinucleotides in RNA viruses infecting mammals 7, 8. Later, an evolutionary survey of influenza A upon transition from avian to human hosts suggested a selection pressure

Large-Scale Synonymous Recoding of Viral Genomes Indicates Innate Detection of Specific Sequences

A popular approach for studying the interaction of the immune system with viral sequence patterns is the large-scale synonymous recoding of viral genomes [15]. Taking advantage of the degeneracy of the genetic code, this strategy consists of replacing whole portions of viral genomes with sequences either enriched for or depleted of the pattern of interest, without altering the protein coding sequence. Pioneering studies introduced rare codons in the capsid-coding region of poliovirus genome and

Sequence Specificity of Known Human Receptors

Several nucleic acid sensors have been proposed or suspected to sense specific microbial sequences, as listed in Table 2. We categorize these receptors depending on two aspects. The first is subcellular localization, since one would hypothesize that the sensitivity of PRRs strongly depends on spatial proximity to self-derived ligands. According to this hypothesis, nucleic acid receptors located in endosomes and cytoplasmic DNA sensors should not bind ligands in a highly sequence-dependent

Sequence Patterns and RNA Decay

Molecular stability is another property linked to nucleic acid sequence (Box 3). Unique sequence elements found at the 3′-end of cellular mRNAs can mediate their degradation, such as AU-rich elements (AREs), which are characterized by a tandem repeat AUUUA sequence or a simple U-rich region [59]. AREs are observed in the sequence of many mRNAs related to the immune response and bind specific proteins, such as AU-binding factor 1 (AUF1), which recognizes AREs and targets mRNAs for rapid

Endogenous Silenced Elements: Sequences and Consequences

Overall, sequences of nucleic acids influence their structure, stability, and recognition by cellular receptors. Interestingly, many human sequences, which are not transcribed under homeostatic conditions, contain sequence patterns that are not observed in the rest of human transcriptome (Figure 1). Recent analysis of their interaction with the innate immune systems has unraveled unexpected new roles for these silenced elements.

During evolution, sequences of foreign origin, predominantly

Concluding Remarks and Future Perspectives

The mammalian immune system relies on a large array of nucleic acid sensors. In recent years, increasingly refined computational studies of host and microbial genomes have greatly improved our understanding of the features that allow the distinction of self and non-self sequences. In parallel, biochemical and structural analyses of nucleic acid sensors have unraveled various degrees of sequence specificity.

Here, we have reviewed both computational and experimental evidence that innate immunity

Acknowledgments

N.V. is grateful to A. Lepelley and C. Melegari for helpful discussion and critical reading of the manuscript. N.B. would like to acknowledge support from the National Institutes of Health 1P30 CA 196521-01, 1R01 CA180913-01, R01 CA180913-01, and the Melanoma Research Alliance. B.D.G. would like to acknowledge support from the National Institutes of Health P01CA087497-1, Stand Up to Cancer, the V Foundation, the Lustgarten Foundation, and the National Science Foundation 1545935, along with

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