Oligonucleotide Motifs That Disappear during the Evolution of Influenza Virus in Humans Increase Alpha Interferon Secretion by Plasmacytoid Dendritic Cells

Jiménez-Baranda, Sonia; Greenbaum, Benjamin; Manches, Olivier; Handler, Jesse; Rabadán, Raúl; Levine, Arnold J.; Bhardwaj, Nina

doi:10.1128/jvi.01908-10

Cited by 55 publications

(66 citation statements)

References 47 publications

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“…The strongest forces suppress CpG and CpG-containing trinucleotides particularly when an A or U is next to the core CpG motif. These results are consistent with the avoidance of CpGs in AU contexts observed in influenza viruses replicating in humans (15,22,23). Given the apparent bias against CpG and UpA, we sought to determine if these motifs were linked.…”

Section: Resultssupporting

confidence: 67%

“…Adaptation of dinucleotide motif use in these elements over time is analogous to the viral mimicry of host patterns of sequence motif use (14,21). When an avian influenza virus enters the human population, one can observe adaptation to analogous patterns emerging over time (14,15,22,23). In that case, mutation rates in influenza are very high, so one can follow these evolutionary adaptations over far shorter time periods.…”

Section: Resultsmentioning

confidence: 99%

“…Experimental evidence has supported this hypothesis (23,38,39). Recently we recast our analysis in the language of statistical physics in a way that is theoretically insightful and computationally efficient (15).…”

Section: Discussionmentioning

confidence: 99%

“…There is a surprising similarity to be drawn between foreign viral nucleotide sequences and select ncRNAs silent in normal cells, yet transcribed in cancer cells, activating innate immunity (23,29,(35)(36)(37). We determined that ncRNAs expressed predominantly in normal cells from humans and mice reflect patterns of nucleotide sequence motif avoidance, such as underrepresentation of CpG-containing sequences and reduced UpA, similar to protein-coding RNA.…”

Section: Discussionmentioning

confidence: 99%

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Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells

Tanne

Muniz

Puzio-Kuter

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Recent studies have demonstrated abundant transcription of a set of noncoding RNAs (ncRNAs) preferentially within tumors as opposed to normal tissue. Using an approach from statistical physics, we quantify global transcriptome-wide motif use for the first time, to our knowledge, in human and murine ncRNAs, determining that most have motif use consistent with the coding genome. However, an outlier subset of tumor-associated ncRNAs, typically of recent evolutionary origin, has motif use that is often indicative of pathogenassociated RNA. For instance, we show that the tumor-associated human repeat human satellite repeat II (HSATII) is enriched in motifs containing CpG dinucleotides in AU-rich contexts that most of the human genome and human adapted viruses have evolved to avoid. We demonstrate that a key subset of these ncRNAs functions as immunostimulatory "self-agonists" and directly activates cells of the mononuclear phagocytic system to produce proinflammatory cytokines. These ncRNAs arise from endogenous repetitive elements that are normally silenced, yet are often very highly expressed in cancers. We propose that the innate response in tumors may partially originate from direct interaction of immunogenic ncRNAs expressed in cancer cells with innate pattern recognition receptors, and thereby assign a previously unidentified danger-associated function to a set of dark matter repetitive elements. These findings potentially reconcile several observations concerning the role of ncRNA expression in cancers and their relationship to the tumor microenvironment.noncoding RNA | genome evolution | cancer immunology

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Section: Resultssupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells

Tanne

Muniz

Puzio-Kuter

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…This fact was reinforced by the emergence of the 2009 H1N1 pandemic (2009 pdm) virus (3)(4)(5). Novel reassortant strains can evade adaptive immunity by introducing antigens to a naïve host population or overly stimulate innate immunity by presenting a new host with abundant nonself molecular signals (6)(7)(8)(9)(10). Moreover, both sequence database studies and in vitro experiments have shown that genome reassortment between strains happens nonrandomly: If two strains coinfect the same cell, their progeny may not sample all possible strain/segment combinations uniformly (11)(12)(13)(14).…”

mentioning

confidence: 99%

Viral reassortment as an information exchange between viral segments

Greenbaum

Poon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Viruses have an extraordinary ability to diversify and evolve. For segmented viruses, reassortment can introduce drastic genomic and phenotypic changes by allowing a direct exchange of genetic material between coinfecting strains. For instance, multiple influenza pandemics were caused by reassortments of viruses typically found in separate hosts. What is unclear, however, are the underlying mechanisms driving these events and the level of intrinsic bias in the diversity of strains that emerge from coinfection. To address this problem, previous experiments looked for correlations between segments of strains that coinfect cells in vitro. Here, we present an information theory approach as the natural mathematical framework for this question. We study, for influenza and other segmented viruses, the extent to which a virus's segments can communicate strain information across an infection and among one another. Our approach goes beyond previous association studies and quantifies how much the diversity of emerging strains is altered by patterns in reassortment, whether biases are consistent across multiple strains and cell types, and if significant information is shared among more than two segments. We apply our approach to a new experiment that examines reassortment patterns between the 2009 H1N1 pandemic and seasonal H1N1 strains, contextualizing its segmental information sharing by comparison with previously reported strain reassortments. We find evolutionary patterns across classes of experiments and previously unobserved higher-level structures. Finally, we show how this approach can be combined with virulence potentials to assess pandemic threats. viral evolution | systems biology | emerging infectious disease R eassortment of segmented viruses is a key mechanism for rapid novel virus creation. At least two human influenza pandemics in the last century were linked to lineages where some number of genomic segments reassorted with a genome of nonhuman origin (1, 2). This fact was reinforced by the emergence of the 2009 H1N1 pandemic (2009 pdm) virus (3-5). Novel reassortant strains can evade adaptive immunity by introducing antigens to a naïve host population or overly stimulate innate immunity by presenting a new host with abundant nonself molecular signals (6-10). Moreover, both sequence database studies and in vitro experiments have shown that genome reassortment between strains happens nonrandomly: If two strains coinfect the same cell, their progeny may not sample all possible strain/segment combinations uniformly (11)(12)(13)(14). These analyses focused on whether it is more likely that pairs of segments from the same strain appear together in reassortments, typically using chi-square tests to establish significance.Because influenza has eight segments, there are 256 possible reassortant viruses when a cell is coinfected by two strains. Each strain type and host cellular environment can influence reassortment differently, so it would seem impossible to predict whether a new pandemic strain can form. However, ...

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