IRF-5 IRF-6 IRF-8/ICSBP
IRF-9/ISGF3r various tissues vIRFs (1-4)
Type I Interferons:
Human IFN-α: Induced by dsRNA via TLR3 Auto-induction Transcription factors IRF-3, IRF-5, IRF-7 Does not appear to require c-Jun.
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
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)
进展
1.干扰素产生与TLR和RLR相关； 2.干扰素的产生受调控； 3.干扰素的信号通路及效应机制； 3. 病毒可以逃逸干扰素的作用； 4.干扰素如何应用与临床实践。
What happens when a virus infects a host?
Innate
Crosstalk
Immediate
Young unimmunized children (no memory) Viruses that replicate quickly -Ebola
Becoming clear innate response required for proper development of adaptive response
Cytokines x Clonal expansion T-cells B-cells
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
Papers Reporting the Discovery of Interferon
Proc. Royal Soc. London 147:258-267, 1957 Proc. Royal Soc. London 147:268-273, 1957
问题：
干扰素到底有多少种? 干扰素在机体抵御病毒感染作用中的作用： 干扰素是如何产生的，如何发挥抗病毒作用 及病毒如何抵抗干扰素的作用？ 为什么部分患者对干扰素治疗无效？ 可否预测患者对干扰素的反应性？ 如何提高干扰素的效果：剂量，配伍？ 有无新的干扰素类似的物质？
Interferons: 50 Years after Their Discovery, There Is Much More to Learn
2007.9.27
What are Interferons?
• Naturally occurring proteins and glycoproteins • Secreted by eukaryotic cells in response to viral infections, tumors, and other biological inducers • Produce clinical benefits for disease states such as hepatitis, various cancers, multiple sclerosis, and many other diseases • Strucurally, they are part of the helical cytokine family which are characterized by an amino acid chain that is 145-166 amino acids long
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?
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?
Mouse IFN-α/β production require activation of NF-kB and IRF-3. IRF3
C-Jun
NF-kB IFNB
PRV IV PRD III PRD I PRD II
Matsumoto Microbiol Immunol 2004. 48:147
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.
Family of Interferon regulatory factors (IRFs)
Members IRF-1 IRF-2 IRF-3 IRF-7 IRF-4 Expressed in various cells various cells all tissues not induced by viral infection or IFN all tissues dependent on IFNa/b singaling restricted to T and B cells not induced by IFNs induced by IFN a/b stimulation restricted to myeloid and lymphoid cells induced by IFN-r, but not by IFN-a/b HHV-8 Function Various Attenuator of ISGF3 Induce IFN-a/b Induce IFN-a/b IgL gene and CD20 gene in B cells, FKBP52, ISG15 unclear unclear @8 facilitates it association with IRF-1, 2, (i)IgL, IFN-r JAK-STAT V1-1. V2-1,2. V3-3,7
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 Adaptive >96 hrs
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
Human interferons and interferon-like proteins
Type I IFN: Type II IFN: IFN-a IFN-b IFN-e IFN-k IFNIFN- r
IFN-like proteins: IL-28A IL-28R1 IL-10R2 IL-28B IL-29
TYPE 1 INTERFERONS
Outcome of Infection
Infection wins Infection loses death live (innate plus adaptive) Studied intensely
Best outcome is Infections killed quickly (innate only) Not studied
Genes pH2 stability Inducers
Principal source
Lymphocytes
Adapted from: Murray, Medical Microbiology, 5th Ed.