Influenza A Virus Infection Induces Viral and Cellular Defective Ribosomal Products Encoded by Alternative Reading Frames

Zanker, Damien; Oveissi, Sara; Tscharke, David C.; Duan, Mubing; Wan, Siyuan; Zhang, Xiaomu; Xiao, Kun; Mifsud, Nicole A.; Gibbs, James S.; Izzard, Leonard; Dlugolenski, Daniel; Faou, Pierre; Laurie, Karen; Vigneron, Nathalie; Barr, Ian G.; Stambas, John; Eynde, Benoı̂t J. Van den; Bennink, Jack R.; Yewdell, Jonathan W.; Chen, Weisan

doi:10.4049/jimmunol.1900070

Cited by 28 publications

(22 citation statements)

References 57 publications

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“…This increase in IFN-α expression was associated with increased numbers of pDCs, which in turn could contribute to the bystander activation of autoreactive T cells. More recently, it was reported that a highly functional CD8+ T cell response is elicited by alternative reading frame (ARF) epitopes encoded by NS1 mRNA of IAV, which might have important implications on IAV-induced autoimmunity [55].…”

Section: Viral Infections and Induction Of Autoimmunitymentioning

confidence: 99%

Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms

Smatti

Cyprian

Nasrallah

et al. 2019

Viruses

436

318

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For a long time, viruses have been shown to modify the clinical picture of several autoimmune diseases, including type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), herpetic stromal keratitis (HSK), celiac disease (CD), and multiple sclerosis (MS). Best examples of viral infections that have been proposed to modulate the induction and development of autoimmune diseases are the infections with enteric viruses such as Coxsackie B virus (CVB) and rotavirus, as well as influenza A viruses (IAV), and herpesviruses. Other viruses that have been studied in this context include, measles, mumps, and rubella. Epidemiological studies in humans and experimental studies in animal have shown that viral infections can induce or protect from autoimmunopathologies depending on several factors including genetic background, host-elicited immune responses, type of virus strain, viral load, and the onset time of infection. Still, data delineating the clear mechanistic interaction between the virus and the immune system to induce autoreactivity are scarce. Available data indicate that viral-induced autoimmunity can be activated through multiple mechanisms including molecular mimicry, epitope spreading, bystander activation, and immortalization of infected B cells. Contrarily, the protective effects can be achieved via regulatory immune responses which lead to the suppression of autoimmune phenomena. Therefore, a better understanding of the immune-related molecular processes in virus-induced autoimmunity is warranted. Here we provide an overview of the current understanding of viral-induced autoimmunity and the mechanisms that are associated with this phenomenon.

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Section: Viral Infections and Induction Of Autoimmunitymentioning

confidence: 99%

Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms

Smatti

Cyprian

Nasrallah

et al. 2019

Viruses

436

318

View full text Add to dashboard Cite

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“…derived from canonical reading frames of coding sequences) and cryptic MAPs (i.e. derived from non-canonical reading frames and non-coding sequences) (35,36). A more practical implication of our work is the integration of both translational (codon arrangements) and post-translational events (e.g., MHC-binding affinity) in predictive algorithms to enhance the predictive modeling of the immunopeptidome for cancer immunotherapy and peptide-based vaccines, where discovery of suitable target antigens remains a formidable challenge (37,38).…”

Section: Discussionmentioning

confidence: 99%

CAMAP: Artificial neural networks unveil the role of codon arrangement in modulating MHC-I peptides presentation

Daouda

Dumont-Lagacé

Feghaly

et al. 2020

Preprint

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MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and neoplastic cells by CD8 T cells. However, accurately predicting the MAP repertoire remains difficult, because only a fraction of the transcriptome generates MAPs. In this study, we investigated whether codon arrangement (usage and placement) regulates MAP biogenesis. We developed an artificial neural network called Codon Arrangement MAP Predictor (CAMAP), predicting MAP presentation solely from mRNA sequences flanking the MAP coding regions, while excluding the MAP-coding codons per se. CAMAP predictions were significantly more accurate when using codon sequences than amino acid sequences. Furthermore, predictions were independent of mRNA expression and MAP binding affinity to MHC-I molecules, and applied to several cell types and species. Combining MAP binding affinity, transcript expression level and CAMAP scores was particularly useful to ameliorate predictions of MAP derived from lowly expressed transcripts. Using an in vitro assay, we showed that varying the synonymous codons in the regions flanking MAP sequences (without changing the amino acid sequence) resulted in significant modulation of MAP presentation at the cell surface. Taken together, our results demonstrate the role of codon arrangement in the regulation of MAP presentation and support integration of both translational and post-translational events in predictive algorithms to ameliorate modeling of the immunopeptidome.

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“…Whether or not the virus makes direct use of uORF proteins, it is clear that the adaptive immune system can recognise epitopes from within their reading frames (Fig 3F). MHC I presentation of uORF-derived peptides poses the risk of an adaptive immune response developing against sNSVs, analogous to the risks posed to IAV by the presentation of alternative reading frames (ARFs) and defective ribosomal products (DRiPs) [61–65]. Indeed, the risks posed by the presentation of uORFs are potentially even higher due to the high conservation of these sequences.…”

Section: Discussionmentioning

confidence: 99%

Upstream translation initiation expands the coding capacity of segmented negative-strand RNA viruses

Sloan

Alenquer

Chung

et al. 2019

Preprint

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Segmented negative-strand RNA viruses (sNSVs) include the influenza viruses, the bunyaviruses, and other major pathogens of humans, other animals and plants. The genomes of these viruses are extremely short. In response to this severe genetic constraint, sNSVs use a variety of strategies to maximise their coding potential. Because the eukaryotic hosts parasitized by sNSVs can regulate gene expression through low levels of translation initiation upstream of their canonical open reading frames (ORFs), we asked whether sNSVs could use upstream translation initiation to expand their own genetic repertoires. Consistent with this hypothesis, we showed that influenza A viruses (IAVs) and bunyaviruses were capable of upstream translation initiation. Using a combination of reporter assays and viral infections, we found that upstream translation in IAVs can initiate in two unusual ways: through non-AUG initiation in virally encoded ‘untranslated’ regions, and through the appropriation of an AUG-containing leader sequence from host mRNAs through viral cap-snatching, a process we termed ‘start-snatching.’ Finally, while upstream translation of cellular genes is mainly regulatory, for sNSVs it also has the potential to create novel viral gene products. If in frame with a viral ORF, this creates N-extensions of canonical viral proteins. If not, it allows the expression of cryptic overlapping ORFs, which we found were highly conserved in IAV and widely distributed in peribunyaviruses. Thus, by exploiting their host’s capacity for upstream translation initiation, sNSVs can expand still further the coding potential of their extremely compact RNA genomes.

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Influenza A Virus Infection Induces Viral and Cellular Defective Ribosomal Products Encoded by Alternative Reading Frames

Cited by 28 publications

References 57 publications

Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms

Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms

CAMAP: Artificial neural networks unveil the role of codon arrangement in modulating MHC-I peptides presentation

Upstream translation initiation expands the coding capacity of segmented negative-strand RNA viruses

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