The pathogenesis and virulence of enterovirus-D68 infection

Ayudhya, Syriam Sooksawasdi Na; Laksono, Brigitta M.; Riel, Debby van

doi:10.1080/21505594.2021.1960106

Cited by 32 publications

(26 citation statements)

References 102 publications

(200 reference statements)

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“…We also show that DMA-135 can inhibit replication of the related EV-D68 Fermon variant ( 22 ) albeit less efficiently than EV-A71. NMR comparison of the SLII structures of EV-A71 and EV-D68 reveal the RNAs adopt similar global folds but different structures within the vicinity of the DMA-135 binding epitope.…”

Section: Introductionmentioning

confidence: 62%

“…Positive strand RNA viruses, like EV-A71 and EV-D68, use the same genomic template for translation and viral RNA synthesis. ( 8, 11, 13, 22 ) Following infection, translation proceeds in the cytoplasm via internal loading of the ribosome onto the IRES. The efficiency by which ribosomes are recruited to the IRES determines the frequency by which the viral life cycle transitions from early to late stages because viral protein products are necessary to synthesize nascent genomic RNA and to form infectious virions.…”

Section: Discussionmentioning

confidence: 99%

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Enterovirus Evolution Reveals the Mechanism of an RNA-Targeted Antiviral and Determinants of Viral Replication

Davila‐Calderon

Penumutchu

et al. 2023

Preprint

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Selective pressures on positive-strand RNA viruses provide opportunities to establish target site specificity and mechanisms of action of antivirals. Here, Enterovirus-A71 revertant viruses with resistant mutations in the SLII IRES domain (SLIIresist) were selected at low doses of the antiviral DMA-135. The EV-A71 revertant viruses were resistant to DMA-135 at concentrations that robustly inhibit replication of wild-type virus. EV-A71 IRES structures harboring the suppressor mutations induced efficient expression of reporter Luciferase mRNA in the presence of non-cytotoxic doses of DMA-135 whereas DMA-135 dose-dependently inhibited Luciferase expression from the wild-type IRES element. NMR studies indicate that the resistant mutations change the structure of SLII at the bulge loop binding site of DMA-135 and at part of an extended surface recognized by host RNA-binding protein AUF1. Comparisons of biophysical analysis of complexes formed between AUF1, DMA-135, or either SLII or SLIIresist show that DMA-135 stabilizes a ternary complex with AUF1-SLII but not AUF1-SLIIresist. Further studies demonstrate that the hnRNP A1 protein retains binding affinity for SLIIresist, illustrating that DMA-135 inhibition and viral resistance do not perturb the SLII-hnRNP A1 arm of the regulatory axis. Taken together, this work demonstrates how viral evolution under selective pressures of small molecules can elucidate RNA binding site specificity, mechanisms of action, and provide additional insights into the viral pathways inhibited by the antiviral DMA-135.

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Section: Introductionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Enterovirus Evolution Reveals the Mechanism of an RNA-Targeted Antiviral and Determinants of Viral Replication

Davila‐Calderon

Penumutchu

et al. 2023

Preprint

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“…L. monocytogenes infection of the CNS is commonly preceded by gastrointestinal infection or colonization [ 36 , 37 ], before the pathogen invades the blood and eventually crosses the blood brain barrier [ 38 ]. Although EV-D68 is primarily a respiratory virus, it may also present with gastrointestinal symptoms [ 39 , 40 ]. The patient in this case was taking prednisone, and presented reporting gastrointestinal symptoms for several days.…”

Section: Discussionmentioning

confidence: 99%

Bacterial ribosomal RNA detection in cerebrospinal fluid using a viromics approach

Kinsella

Edridge

Zeggeren

et al. 2022

Fluids Barriers CNS

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Background In patients with central nervous system (CNS) infections identification of the causative pathogen is important for treatment. Metagenomic next-generation sequencing techniques are increasingly being applied to identify causes of CNS infections, as they can detect any pathogen nucleic acid sequences present. Viromic techniques that enrich samples for virus particles prior to sequencing may simultaneously enrich ribosomes from bacterial pathogens, which are similar in size to small viruses. Methods We studied the performance of a viromic library preparation technique (VIDISCA) combined with low-depth IonTorrent sequencing (median ~ 25,000 reads per sample) for detection of ribosomal RNA from common pathogens, analyzing 89 cerebrospinal fluid samples from patients with culture proven bacterial meningitis. Results Sensitivity and specificity to Streptococcus pneumoniae (n = 24) before and after optimizing threshold parameters were 79% and 52%, then 88% and 90%. Corresponding values for Neisseria meningitidis (n = 22) were 73% and 93%, then 67% and 100%, Listeria monocytogenes (n = 24) 21% and 100%, then 27% and 100%, and Haemophilus influenzae (n = 18) 56% and 100%, then 71% and 100%. A higher total sequencing depth, no antibiotic treatment prior to lumbar puncture, increased disease severity, and higher c-reactive protein levels were associated with pathogen detection. Conclusion We provide proof of principle that a viromic approach can be used to correctly identify bacterial ribosomal RNA in patients with bacterial meningitis. Further work should focus on increasing assay sensitivity, especially for problematic species (e.g. L. monocytogenes), as well as profiling additional pathogens. The technique is most suited to research settings and examination of idiopathic cases, rather than an acute clinical setting.

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“…In addition, other viral-mediated cardiovascular diseases among RNA viral infections have been reported. Human patients have been shown to develop myocarditis and pericarditis after subsequent WNV and enterovirus D68 (EV-D68) infections 33,34 . Recently, it has been shown that SARS-CoV-2 is responsible for multiple cardiovascular (CV) manifestations [35][36][37] and can infect human cardiomyocytes 38,39 .…”

Section: Antiviral Compounds Prevent Viral Infection Of Cardiomyocytesmentioning

confidence: 99%

Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses

García

Irudayam

Jeyachandran

et al. 2023

Preprint

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RNA viruses continue to remain a clear and present threat for potential pandemics due to their rapid evolution. To mitigate their impact, we urgently require antiviral agents that can inhibit multiple families of disease-causing viruses, such as arthropod-borne and respiratory pathogens. Potentiating host antiviral pathways can prevent or limit viral infections before escalating into a major outbreak. Therefore, it is critical to identify broad-spectrum antiviral agents. We have tested a small library of innate immune agonists targeting pathogen recognition receptors, including TLRs, STING, NOD, Dectin and cytosolic DNA or RNA sensors. We observed that TLR3, STING, TLR8 and Dectin-1 ligands inhibited arboviruses, Chikungunya virus (CHIKV), West Nile virus (WNV) and Zika virus, to varying degrees. Cyclic dinucleotide (CDN) STING agonists, such as cAIMP, diABZI, and 2',3'-cGAMP, and Dectin-1 agonist scleroglucan, demonstrated the most potent, broad-spectrum antiviral function. Comparative transcriptome analysis revealed that CHIKV-infected cells had larger number of differentially expressed genes than of WNV and ZIKV. Furthermore, gene expression analysis showed that cAIMP treatment rescued cells from CHIKV-induced dysregulation of cell repair, immune, and metabolic pathways. In addition, cAIMP provided protection against CHIKV in a CHIKV-arthritis mouse model. Cardioprotective effects of synthetic STING ligands against CHIKV, WNV, SARS-CoV-2 and enterovirus D68 (EV-D68) infections were demonstrated using human cardiomyocytes. Interestingly, the direct-acting antiviral drug remdesivir, a nucleoside analogue, was not effective against CHIKV and WNV, but exhibited potent antiviral effects against SARS-CoV-2, RSV (respiratory syncytial virus), and EV-D68. Our study identifies broad-spectrum antivirals effective against multiple families of pandemic potential RNA viruses, which can be rapidly deployed to prevent or mitigate future pandemics.

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The pathogenesis and virulence of enterovirus-D68 infection

Cited by 32 publications

References 102 publications

Enterovirus Evolution Reveals the Mechanism of an RNA-Targeted Antiviral and Determinants of Viral Replication

Enterovirus Evolution Reveals the Mechanism of an RNA-Targeted Antiviral and Determinants of Viral Replication

Bacterial ribosomal RNA detection in cerebrospinal fluid using a viromics approach

Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses

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