WELCOME TO MY PRESENTATION Molecular Players in Host-Virus Interaction: Novel roles for microRNAs Presented by: Jahed Ahmed Reg. No. 2008432018
Virus - Host Interaction Immune Persistance response Cell Virus signallinginfection Clearance Apoptosis Fig.:Viruses interact with three basic host responses
Host-Virus interaction1. Essential for virus function -Replication -Movement2. Host Resistance Interactions3. Inconsequential to virus function Virus Host Disturbance in the host physiology Proteome Transcriptome Disease/Resistance Metabolic Pathways etc.
MicroRNAs• microRNAs (miRNAs) are small noncoding RNAs of ∼ 22-nt length that serve as posttranscriptional regulators of gene expression in higher eukaryotes• First identified in 1993 in C. elegans by Ambross• But in 2001 it got the attention of researchers when it is found to be related in cancer• These small non-coding RNAs can contribute to the repertoire of host pathogen interactions during viral infection• Host-cellular miRNAs modulating the expression of various viral genes, thereby playing a pivotal role in the host–pathogen interaction network
MicroRNAs• Viruses have evolved highly sophisticated gene- silencing mechanisms to evade host-immune response• Recent reports indicate that virus too encode miRNAs that protect them against cellular antiviral response• The host–virus interaction at the molecular level lead us toward possible explanations to viral tropism, latency and oncogenesis along with the development of an effective, durable and nontoxic antiviral therapy• It is reported that least 30% human genes are regulated by miRNAs
Biogenesis of MicroRNAsMicroRNAs are transcribed by the RNA polymerase IIenzyme to produce a primary-microRNApri-microRNAs form specific hairpin secondary structures andenter a microprocessor complexThe pre-miRNAs are then transported to the cytoplasmIn the cytoplasm, pre-miRNAs are further processed to a shortdouble strand miRNA duplex by DicerThen association with RISC (RNA induced silencing complex)2 mechanisms of action: inhibition of translation OR mRNAcleavage
microRNA Biogenesis and action Dicer miRNA-miRNA* pre-miRNA miRNA with RISC Messenger RNA AAAAA Exportin 5 Drosha/Pasha Transcript Degradation pri-miRNA Transcript P Bodies RNAPol II PolypeptideScaria et al. Retrovirology 2006
Five Human microRNAs can possibly target HIV genes
Human microRNAs target HA and PB2 genes in Influenza A/H5N1 genome Polymerase PB2SEGMENT1 hsa-mir-507 responsible for RNA replication and transcription Hemagglutinin (HA)SEGMENT4 hsa-mir-136 facilitates entry of the virus into the cell
Mechanisms of microRNAs in viral oncogenesis Altered host gene expression Viral encoded Viral genome microRNAs integration and mutations Regulatory dysfunction Oncogenesis Virus induced epigenetic changes Viral suppression of RNAi Altered host microRNA expressionScaria and Jadhav, Retrovirology, 2007
Scaria and Jadhav, Retrovirology. 2007 Nov 24;4(1):82 Host-Pathogen Interaction: An integrative Model for microRNAs in viral oncogenesisVirus encoded proteinsand cell signalingmediated by viral PROTEIN INTERACTION AND SIGNALLINGinfections microRNA mediated regulationVirus encoded POST-TRANSCRIPTIONAL REGULATIONmicroRNAsVirus encodedsuppressors of RNAi SPLICING AND RNA EDITINGViral encodedtranscriptionalregulators TRANSCRIPTIONAL REGULATIONViral Genomeintegration GENOME STRUCTURE AND CHROMATIN ORGANISATIONChromosomal GENOME SEQUENCEInstabilitiesEpigenetic Changes
Viral miRNAs-Regulating Gene Expression:Fig.: Effects of virus-encoded microRNAs on viral andcellular transcripts.
Future Prospects•MicroRNA as a novel arm of gene expressional regulationtool has great potential to be employed in drug development•miRNA research may provide us more insights and improvedunderstanding towards miRNA biogenesis, function andparticularly their association with molecular pathogenesis of avariety of complex diseases including cancer, heart diseases,chronic viral infections, immune disorders, neurodegenerativedisease and metabolic diseases.•Identify oncogenic miRNAs, and viral encoded miRNAs,which may key factors for viral replication and latency and theideal targets for developing therapeutics•Design of artificial antiviral microRNAs (amiRNAs) whichmay be used as therapeutics
Conclusions•The integral role of miRNAs in controlling various complexregulatory networks within a cell is gradually coming intolimelight. It is seen that host-encoded miRNAs have bothpositive and negative modulatory effect on viral replication.•Virus uses their own miRNA induced gene-silencingmachinery to protect them against the cellular antiviral RNAiresponse and may even affect cellular gene expression.•miRNA-induced gene-silencing approach holds great promisefor selectively inhibiting virus-specific genes or host genes forthe treatment of viral infections.•The miRNA-mediated host–virus interaction at the molecularlevel, which will lead toward the development of effective non-toxic antiviral therapy.
Summary Human microRNAs have conserved targets in viral genes Viral microRNAs may miRNA-miRNA* influence cellular biological processes Dicer resulting in oncogenesis pre-miRNA Exportin 5 miRNA with RISC Drosha miRNA levels in Human Transcript can be used as a Transcript molecular marker for pri-miRNA disease susceptibility and prognosis.RNAPol II P Bodies Degradation NUCLEUS Polypeptide Synthetic/Artifical CYTOPLASM miRNAs or miRNA analogs may be used as therapeutics
References1.Lecellier CH, et al. A cellular microRNA mediates antiviral defense inhuman cells. Science 2005;308:557–560. [PubMed: 15845854]2.Pedersen IM, et al. Interferon modulation of cellular microRNAs as anantiviral mechanism. Nature 2007;449:919–922. [PubMed:17943132]3.Bartel DP: MicroRNAs: genomics, biogenesis, mechanism,and function. Cell 2004, 116:281-297.4.Esquela-Kerscher A, Slack FJ: Oncomirs [mdash] microRNAs with a role incancer. Nat Rev Cancer 2006, 6:259-269.5.John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS: HumanMicroRNA targets. PLoS Biol 2004, 2:e363.6.Browne, E.P., Li, J., Chong, M., and Littman, D.R. (2005) Virus–hostinteractions: new insights from the small RNA world. Genome Biol 6: 238.7.Nair,V. and Zavolan,M. (2006) Virus-encoded microRNAs: novelregulators of gene expression. Trends Microbiol., 14, 169–175.8. Cullen,B.R. (2006) Viruses and microRNAs. Nature Genet., 38, S25–S30.