Virology

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Chapter 33 notes: Intrinsic cellular defense against virus infection

1. Toll- like receptors sense virus infections
a. Toll-like receptors (TRL)
i. Located on the cell surface or in endosomal membranes = recognize conserved structures found in pathogens ii. Highly conserved receptors from flies humans
iii. Most mammals have between 10-15 (humans = 10)
iv. TLR – 2: lipoproteins/glycoproteins (mealsels, hepB, herpes) v. TLR– 3: dsRNA (west nile, influenza)
vi. TLR – 5: flagellin
vii. TLR – 7/8: ssRNA: (HIV, influenza..)
1. Recognize the guanine and uridine rich single stranded RNAs) viii. TLR 9: unmethlylated CpG DNA (vaccinia, hepB, herpes) 2. Both single and dsDNA
b. Many DNA viruses transcribe both strands of certain regions of their DNA genomes = self- complementary RNAs (dsRNA) c. ssRNA viruses = replicate their genome by synthesizing full length complementary RNA stands that can form dsRNA by hybridizing to the template RNA strand ix. ***The presence of dsRNA is the MOST RELIABLE indicator that a replicating virus is present*** x. TLR 3- recognizes dsRNA

xi. Expression of TLR3 is found on many cells – dendritic cells, macrophages, fibroblasts, epithelial cells xii. ****only binds to dsRNA at a low pH indicating that it happens in endosomes 2. Detection of viral RNAs:

d. RIG-I (RNA helicase, retinoic acid inducible gene I) xiii. short dsRNA, ssRNA with a 5’ triphosphate group e. MDA 5 (melanoma differentiation association gene 5) xiv. Long dsRNA

f. *both recognize RNAs from different viruses
g. *unlike the TLR they are soluble and cytosolic proteins that can bind to ncleic acids localized in the cytosol 3. Recognition of dsDNA in the cytoplasm (three different cellular components) h. *sign of infection because dsDNA is not generally found in the cytoplasm in health cells i. DNA- dependent activator of interferon (DAI) regulatory factors xv. Expressed on most cell types

xvi. Recognition of cytosolic DNA by DAI leads mainly to the production of interferon j. AIM2
k. NLRP3 protein
xvii. Both are involved in the production of inflammatory cytokines 4. Response of the cell to virus infection
l. Cellular detector proteins initiate signal transduction pathways that activate a variety of transcription factors m. Interferon- stimulated genes (ISG)
n. The cytosolic detector proteins (RIG-I) and MDA5 recruit the adapter proteins interferon-B promoter stimulator I (IPS-1) – interaction of IPS1 with additional cellular proteins leads to the activation of IKK and TBK1 and the nuclear translocation 5. Cellular recognition of virus infection leads to production of cytokines o. Cytokines – are stimulated protective reactions in the infected host p. Proteins produced are involved in protecting the cell from virus infection or activating the immune system xviii. Interferons:

xix. Proinflammatory cytokines:
3. (interleukins 1,6,12, tumor necrosis factor a) 4. activate immune cells within the circulatory system xx. chemokines
5. recruit immune cells (lymphocytes and antigen presenting cells) xxi. antionflammatory cytokines
6. suppress the proinflammatory cytokines
6. Recognition of virus infection can trigger death in infected cells q. Apoptosis:
xxii. Death results from the activation of caspases (cysteine proteases that cleave after aspartate residues) xxiii. These proteases are normally present in inactivate ‘procaspases’ xxiv. TWO main pathways:

7. Extrinsic – triggered by cell surface receptor a. If TNFa binds to a cellular receptor then..trimerization of the receptor –...
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