Seminar presentation on host-virus interaction

1. WELCOME TO MY PRESENTATION
Molecular Players in Host-Virus
Interaction:
Novel roles for microRNAs
Presented by:
Jahed Ahmed
Reg. No. 2008432018

2. Virus - Host Interaction
Immune Persistance
response Cell
Virus
signalling
infection Clearance
Apoptosis
Fig.:Viruses interact with three basic host responses

3. Host-Virus interaction
1. Essential for virus function
-Replication
-Movement
2. Host Resistance Interactions
3. Inconsequential to virus function
Virus Host
Disturbance in the host physiology
Proteome
Transcriptome Disease/Resistance
Metabolic Pathways etc.

4. 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

5. 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

6. Biogenesis of MicroRNAs
MicroRNAs are transcribed by the RNA polymerase II
enzyme to produce a primary-microRNA
pri-microRNAs form specific hairpin secondary structures and
enter a microprocessor complex
The pre-miRNAs are then transported to the cytoplasm
In the cytoplasm, pre-miRNAs are further processed to a short
double strand miRNA duplex by Dicer
Then association with RISC (RNA induced silencing complex)
2 mechanisms of action: inhibition of translation OR mRNA
cleavage

7. 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 Polypeptide
Scaria et al. Retrovirology 2006

8. Model of microRNA mediated host-virus crosstalk
MODEL-II MODEL-III
DICER RISC
MODEL-IV
MODEL-I
EXPORTIN
DROSHA/P
ASHA
Host Transcript
Host Transcript
Polypeptide Viral Transcript
Viral Transcript
RNAPol II
Scaria et al. Retrovirology 2006

9. Five Human microRNAs can possibly target
HIV genes

10. Human microRNAs target HA and PB2 genes
in Influenza A/H5N1 genome
Polymerase PB2
SEGMENT1
hsa-mir-507
responsible for
RNA replication and
transcription Hemagglutinin (HA)
SEGMENT4
hsa-mir-136
facilitates entry of
the virus into the
cell

11. 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
expression
Scaria and Jadhav, Retrovirology, 2007

12. Scaria and Jadhav, Retrovirology. 2007 Nov 24;4(1):82
Host-Pathogen Interaction: An integrative
Model for microRNAs in viral oncogenesis
Virus encoded proteins
and cell signaling
mediated by viral PROTEIN INTERACTION AND SIGNALLING
infections microRNA
mediated
regulation
Virus encoded
POST-TRANSCRIPTIONAL REGULATION
microRNAs
Virus encoded
suppressors of RNAi
SPLICING AND RNA EDITING
Viral encoded
transcriptional
regulators TRANSCRIPTIONAL REGULATION
Viral Genome
integration
GENOME STRUCTURE AND CHROMATIN ORGANISATION
Chromosomal
GENOME SEQUENCE
Instabilities
Epigenetic Changes

13. Viral miRNAs-Regulating Gene Expression:
Fig.: Effects of virus-encoded microRNAs on viral and
cellular transcripts.

14. Future Prospects
•MicroRNA as a novel arm of gene expressional regulation
tool has great potential to be employed in drug development
•miRNA research may provide us more insights and improved
understanding towards miRNA biogenesis, function and
particularly their association with molecular pathogenesis of a
variety of complex diseases including cancer, heart diseases,
chronic viral infections, immune disorders, neurodegenerative
disease and metabolic diseases.
•Identify oncogenic miRNAs, and viral encoded miRNAs,
which may key factors for viral replication and latency and the
ideal targets for developing therapeutics
•Design of artificial antiviral microRNAs (amiRNAs) which
may be used as therapeutics

15. Conclusions
•The integral role of miRNAs in controlling various complex
regulatory networks within a cell is gradually coming into
limelight. It is seen that host-encoded miRNAs have both
positive and negative modulatory effect on viral replication.
•Virus uses their own miRNA induced gene-silencing
machinery to protect them against the cellular antiviral RNAi
response and may even affect cellular gene expression.
•miRNA-induced gene-silencing approach holds great promise
for selectively inhibiting virus-specific genes or host genes for
the treatment of viral infections.
•The miRNA-mediated host–virus interaction at the molecular
level, which will lead toward the development of effective non-
toxic antiviral therapy.

16. 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

17. References
1.Lecellier CH, et al. A cellular microRNA mediates antiviral defense in
human cells. Science 2005;308:557–560. [PubMed: 15845854]
2.Pedersen IM, et al. Interferon modulation of cellular microRNAs as an
antiviral 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 in
cancer. Nat Rev Cancer 2006, 6:259-269.
5.John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS: Human
MicroRNA targets. PLoS Biol 2004, 2:e363.
6.Browne, E.P., Li, J., Chong, M., and Littman, D.R. (2005) Virus–host
interactions: new insights from the small RNA world. Genome Biol 6: 238.
7.Nair,V. and Zavolan,M. (2006) Virus-encoded microRNAs: novel
regulators of gene expression. Trends Microbiol., 14, 169–175.
8. Cullen,B.R. (2006) Viruses and microRNAs. Nature Genet., 38, S25–S30.