Involvement of host microRNAs in flavivirus-induced neuropathology: An update

Majumdar, Atreye; Basu, Anirban

doi:10.1007/s12038-022-00288-1

Cited by 7 publications

(3 citation statements)

References 160 publications

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“…Among these five proteins, we identify DDX1, an important helicase involved in host-defense mechanisms during viral infections [39]. NKRF is a regulator of DHX15, another RNA helicase involved in RNA processing and antiviral innate immunity [40], which was also seen to be inhibited by miR-301a during JEV infection [41]. Another example is NUFP2, a FMR1-interacting protein directly antagonized by the sfRNA of ZIKV [42].…”

Section: Resultsmentioning

confidence: 99%

Subgenomic flaviviral RNAs and human proteins:in silicoexploration of anti-host defense mechanisms

Ponti,

Vandelli,

Tartaglia

2024

Preprint

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BackgroundFlaviviruses pose significant global health threats, infecting over 300 million people annually. Among their evasion strategies, the production of subgenomic flaviviral RNAs (sfRNAs) from the 3’ UTR of viral genomes is particularly notable. These sfRNAs interact with human proteins, disrupting key cellular processes such as RNA splicing and the interferon response.ResultsUtilizing a comprehensivein silicoapproach with thecatRAPID algorithm, we analyzed over 300,000 interactions between sfRNAs and human proteins derived from more than 8,000 flavivirus genomes, including Dengue, Zika, Yellow Fever, West Nile, and Japanese Encephalitis viruses. Our study not only validated known interactions but also revealed novel human proteins that could be involved in sfRNA-mediated host defense evasion, including helicases, splicing factors, and chemokines. We propose that sfRNAs function as molecular sponges, sequestering specific proteins indicative of sfRNA-forming regions across flaviviruses. These findings represent a valuable resource for diagnostic and therapeutic developments.ConclusionsOur findings significantly expand the known interactome of sfRNAs with human proteins, underscoring their role in modulating host cellular pathways. By providing the first extensive atlas of sfRNA interactions, we offer new insights into how flaviviruses can manipulate host cellular machinery to facilitate viral survival and persistence. Intriguingly, we predict interaction with stress granules, a critical component of the cellular response to viral infection, suggesting a mechanism by which flaviviruses inhibit their formation to evade host defenses. This atlas not only serves as a resource for exploring therapeutic targets but also aids in the identification of sfRNA biomarkers for improved flavivirus diagnostics.

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Section: Resultsmentioning

confidence: 99%

Subgenomic flaviviral RNAs and human proteins:in silicoexploration of anti-host defense mechanisms

Ponti,

Vandelli,

Tartaglia

2024

Preprint

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“…Building upon initial observations, we posited that SCFAs could modulate microglial function by intricately adjusting their miRNA profiles, thereby influencing key inflammatory pathways. Previous studies have established the pivotal role of miRNAs in a host of cellular mechanisms, especially in the context of flavivirus infections ( 38 ). A pertinent question for future research is whether the shifts we observed in miRNA expression profiles and their downstream effects are attributable to HDAC inhibition.…”

Section: Discussionmentioning

confidence: 99%

Short-chain fatty acids abrogate Japanese encephalitis virus-induced inflammation in microglial cells via miR-200a-3p/ZBTB20/IKβα axis

Majumdar,

Siva Venkatesh,

Swarup

et al. 2024

mBio

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Japanese encephalitis virus (JEV), a member of the Flaviviridae family, is a leading cause of viral encephalitis in humans. Survivors of this infection often develop lifelong neurological sequelae. Short-chain fatty acids (SCFAs) produced in the gut are vital mediators of the gut-brain axis. We aimed to study microRNA-based mechanisms of SCFAs in an in vitro model of JEV infection. N9 microglial cells were pretreated with SCFA cocktail before JEV infection. Cytokine bead analysis, immunoblotting, and PCR were performed to analyze relevant inflammatory markers. microRNA sequencing was performed using Illumina Hiseq, and bioinformatics tools were used for differentially expressed (DE) miRNAs and weighted gene co-expression network analysis (WGCNA). microRNA mimic/inhibitor experiments and luciferase assay were performed to study miRNA-target interaction. A significant reduction in monocyte chemoattractant protein (MCP1) and tumor necrosis factor alpha (TNFα) along with reduced expression of phospho-nuclear factor kappa B (phospho-NF-κB) was observed in SCFA conditions. Significant attenuation of histone deacetylase activity and protein expression was recorded. miRNA sequencing revealed 160 DE miRNAs in SCFA + JEV-treated cells at 6 h post-infection. WGCNA revealed miR-200a-3p, a hub miRNA significantly upregulated in SCFA conditions. Transcription factor ZBTB20 was bioinformatically predicted and validated as a gene target for miR-200a-3p. Further miRNA mimic/inhibitor assay demonstrated that miR-200-3p regulated ZBTB20 along with Iκβα that possibly dampened NF-κB signal activation downstream. IMPORTANCE The gut-brain axis plays a pivotal role in the physiological state of an organism. Gut microbiota-derived metabolites are known to play a role in brain disorders including neuroviral infections. Short-chain fatty acids (SCFAs) appear to quench inflammatory markers in Japanese encephalitis virus-infected microglial cells in vitro . Mechanistically, we demonstrate the interaction between miR-200a-3p and ZBTB20 in regulating the canonical nuclear factor kappa B (NF-κB) signaling pathway via transcriptional regulation of Iκβα. Findings of this study pave the way to a better understanding of SCFA mechanisms that can be used to develop strategies against viral neuroinflammation.

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“…These multifarious molecules wield the potential to impact viral replication, temper the host's inflammatory response, fine-tune the expression of signaling molecules, and even shape the presentation of viral antigens. This discernment unveils an additional stratum of complexity within the molecular apparatus that underpins the intricate interplay between viruses and their hosts [5].…”

Section: Introductionmentioning

confidence: 93%

Exploring the Interactions between Human microRNAs and the Ilheus Virus Genome

Souza,

Casseb

2023

SynBio

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MicroRNAs (miRNAs) are small non-coding RNA molecules that play a fundamental role in the regulation of gene expression in humans. There has been a growing interest in investigating the interactions between human miRNAs and viruses to better understand the underlying mechanisms of the immune response and viral pathogenesis. The Ilheus virus, an arbovirus transmitted by mosquitoes, is known to cause disease in humans, with symptoms ranging from mild fever to severe neurological complications. This scientific article aims to explore the potential role of human miRNAs in their association with the genome of the Ilheus virus. Previous research has indicated that miRNAs can affect viral replication and the host’s immune response, playing a critical role in modulating the virus–host interaction. Here, we will investigate the possible interactions between specific human miRNAs and regions of the Ilheus virus genome, focusing on identifying miRNAs that may impact viral replication or the host’s immune response. A search for potential human miRNAs associated with the viral genome of ILHV was conducted through database searches such as miRBase. For the elucidation of targets regulated by these miRNAs, the TargetScan program was adopted. Functional enrichment analysis, inferring the function of genes regulated by miRNAs, was provided by the DAVID software. To elucidate the secondary structure, tools hosted in the RNAFold repositories were employed. In summary, our research has identified miRNAs linked to crucial sections of the Ilheus virus genome. These miRNAs can potentially regulate genes associated with neurological and immune functions. This highlights the intricate interplay between human miRNAs and the Ilheus virus genome, suggesting a pivotal role for these molecules in the host’s response to viral infections.

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Involvement of host microRNAs in flavivirus-induced neuropathology: An update

Cited by 7 publications

References 160 publications

Subgenomic flaviviral RNAs and human proteins:in silicoexploration of anti-host defense mechanisms

Subgenomic flaviviral RNAs and human proteins:in silicoexploration of anti-host defense mechanisms

Short-chain fatty acids abrogate Japanese encephalitis virus-induced inflammation in microglial cells via miR-200a-3p/ZBTB20/IKβα axis

Exploring the Interactions between Human microRNAs and the Ilheus Virus Genome

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