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Innate Host Responses to Viral Infection 1

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					Innate Host Responses to Viral Infection 1.
MICR3002. Dr Nigel McMillan Centre for Immunology and Cancer Research.

Complete lecture with notes and summary lecture podcast* (with slides) available at
www.cicr.uq.edu.au/students * Plays in iTunes or Quicktime (free from apple.com)

Peloponnesian War and Thucydides
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What happens when a virus infects a host?
Innate
Crosstalk

Immediate

Adaptive

Delayed (1-2 weeks)

The innate immune responses are •present from birth •non-specific •do not become more efficient over time (but there is evolutionary selection)

Outcome of Infection
• Infection wins • Infection loses death live (innate plus adaptive) Studied intensely

Best outcome is • Infections killed quickly (innate only) Not studied
How is it that most people are not perpetually sick? (Innate immunity squelching most infections)

Process of infection
Initial 0-4 hrs Innate 4-96 hrs Cytokines
x Clonal expansion T-cells B-cells

Adaptive >96 hrs

x

NK Cell

Memory

Do we need an innate response?
• Yes - major role is limiting initial infection to a manageable level • Adaptive not quick enough to protect
– Young unimmunized children (no memory) – Viruses that replicate quickly -Ebola

• Becoming clear innate response required for proper development of adaptive response

Mice with No Innate response to Virus
KO

Heterozygote

Normal

Transgenic mice missing the gene required for innate response infected with SFV

What is Innate Immunity?
• Initial recognition of infection (Toll-like receptors, dsRNA-based defenses • Response - Cytokine-mediated responses (Interferon, TNF, IL-1, etc) • cell-mediated (NK cells) • Mechanical - mucus etc Why bother studying this? Viral drugs - how many? Could be the best way to deal with infection New viruses

Recognition of viral infection
How does a cell know its infected and what can it do about it?

How are pathogens recognized?
i.e. what turns on innate responses?

Toll-like receptors (TLRs)
• pattern recognition receptors • Can identify a foreign invader (virus, bacterial, etc) via a conserved microbial product and initiate the innate response • 9 identified so far

Toll-like receptor pairs
Cell surfaces
a. b. c. d. TLR-1/TLR-2 -bacterial lipopeptides and GPI-anchored proteins in parasites; TLR-2/TL6 - lipoteichoic acid from grampositive cell walls and zymosan from fungi; TLR-4/TLR-4 -LPS from gram-negative cell walls TLR-5* - bacterial flagellin

Endosomes a. TLR-3* - dsRNA

b. TLR-7* -uracil-rich single-stranded viral RNA (HIV)
c. TLR-8* - single-stranded viral RNA d. TLR-9* - unmethylated CpG DNA found in bacterial and viral genomes.

*other member of pair is unknown
Key: Different combinations of TLRs appear in different cell types and seem to appear as TLR pairs.

dsRNA

TLR3

IRF7

Interferon Regulatory Factor 3

IFNb

Antiviral Response

dsRNA appears to do something else

RNA-interference
• • • • RNA-based gene regulation and defense mechanism used for control of our own genes (miRNA) recognition of viruses (dsRNA) Controls gene expression by
– Degrading mRNA complimentary to dsRNA – Inhibit mRNA translation into protein – Turn off gene by heterochromatin remodeling

• Many plant viruses encode suppressors of RNAi • Important in antiviral defense?

QuickTime™ and a H.263 decompressor are needed to see this picture.

http://www.nature.com/focus/rnai/animations/

RNA Interference
C 1nM 5nM 10nM 20nM 40nM

Lung Metastasis
Con
E7 Tubulin

HPV16E6 Seq. 10

Cancer

Cancer + con siRNA

Cancer + siRNA

How do we recognize dsRNA as viral rather than endogenous?
The 3’, 2bp overhang of siRNA/miRNAs are “self” signals

April 30, 2006 Advanced online publication

Response: Cytokines
• Small soluble proteins made by one cell that can effect the behavior of that or other cells • interact with specific receptors and signal transduction pathways to elicit major changes in cell behavior INTERFERON, TNF, IL-1

Important cytokines
IFN-a/b TNF-a Infection IL-1 IL-12 Fever, Direct antiviral effects Activates NK cells Fever, shock Fever, IL-6 production Activates NK cells, signals adaptive immune response

Interferon
“Interferons are protein components of animal cells which are synthesized and excreted under a variety of stimuli and make other cells of the same species incapable of replicating virus”.
DeSomer and Cocito 1968

Issac and Linderman’s Discovery (1957)
Cells plus heat-inactivated Influenza virus

Discard cells and transfer supernatant onto new cells

Incubate Overnight

Incubate Overnight then add live virus
NO INFECTION

IFN

Protect cells against viral infection

IFN-deficient patient.
Before

IFN therapy

What induces IFN?
• Something in viruses
– Influenza virus - heat and UV treated  – DNA viruses inactivated  normal  DNA viruses need to replicate: RNA viruses do not

dsRNA is best activator of IFN genes.

IFN is induced by many other substances

• viruses DNA (active) and RNA (active and inactive) • rickettsia • bacteria (esp. gram-negative) • live/killed mycoplasma • protozoa • nucleic acids esp. dsRNA

Biological Activities of IFN
Signal

ISG
IFN-induced protein

Inhibition of viral replication Inhibition of Cell Growth Regulation of Cell differentiation

Activation of Immune System

What is the basis of species specificity?
Add Human IFa Bind? Activity? Mouse Cell  

+Hu IFNa/bR





+ Hu IFNgR





-IFNa/b share receptor, IFNg has its own, & receptor is species barrier

dsRNA

TLR3

IRF7

Interferon Regulatory Factor 3

IFNb

JAK/STAT

Mx

Antiviral proteins

Virus Death

PKR
2-5A

Virus sensitivity to IFNs
Small RNA viruses - picornaviruses

Large RNA viruses - Flu, rotovirus

Small DNA viruses - papillomavirus

Large DNA viruses - Herpes, poxvirus

Clinical Use of IFN
• Viral Infections
– Hepatitis B and C – HPV warts – RSV

• Cancer

Other conditions

– Hairy cell Leukemia (90% effective) – Follicular lymphoma – cervical (HPV) – basal cell cancer (8090%) – Kaposi’s sarcoma (HHV type 8) - chronic granulomatous disease (IFN-g) - multiple sclerosis

Clinical use cont.
• A powerful drug
– acts like a blunderbuss – Not a magic bullet – Overused - oral verses systemic

• us$4 billion in 1999 • Confounded by non-responders
– 1/3 respond – 1/3 respond and relapse – 1/3 non-response.

Learning Objectives
• Understand the parts of the innate immune system against viruses • Mechanism of RNA interference • Specificity of IFN • Viral sensitivity to the IFN systems

Next time The viruses fight back!


				
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