19
Virology (MD PhD) (Fach) / Pavlovic (Lektion)
Anzeige
- Interferons IFN-λ: antiviral response in the gastrointestinal or respiratory mucosae IFN-α/β: acts on all cells
- Activation of TLRs by PAMPs dsRNA --> TLR3 LPS --> TLR4 ssRNA --> TLR7 Bacterial or viral DNA (CpG) --> TLR9 --> activation of NF-KB
- RNA virus sensors localized in the cytoplasm - RIG-1 (Helicase) --> IFN ß Production- MDA5 (Helicase)- PKR (prevents translation) --> Apoptosis- OAS (RNase) --> Apoptosis
- DNA virus sensors localized in the cytoplasm - RNA polymerase III- AIM2- IFI16 or p204- cGAS --> merge at STING activation
- Viral Hepatitis Hepatitis A Virus (HAV) - Picornaviridae - ssRNA(+) Hepatitis B virus (HBV) - Hepadnaviridae - dsDNA (partial) Hepatitis C Virus (HCV) - Flaviviridae - ssRNA(+) Hepatitis delta Virus (HDV) - circular, ssRNA(-) Hepatitis E Virus (HEV) - ssRNA(+)
- Hepatitis B virus - surface glycoprotein: HBsAg- L protein: essential for attachment and entry Core- HBeAg (pre core) - HBcAg (core) - not covalently closed circular DNA - The (−)strand DNA is covalently linked to the P protein (priming of reverse transcription) - 95% of the infected adults clear the infection, 5% remain chronically infected - Risk: Development of liver cirrhosis and liver carcinoma (HCC) 30 to 50 years after infection
- HBsAg Marker - if patient has antibodies against HBsAg --> acute infection with recovery - if patient only has HBsAg in serum and no antibodies (but antibodies against HBeAg, HBcAg) --> chronic infection
- Structure of HBV particles (infectious and noninfectious) Infected cells produce many more non-infectious (spheres) than infectious particles The spheres may represent a decoy for antibodies
- HBV Life cycle - Relaxed circular viral DNA moves to the nucleus where it is repared, forming a closed, circular cccDNA - The cccDNA is template for transcription(HBV persists episomally as cccDNA) - Transcription is carried out by the cellular RNA polymerase II - Reverse transcriptase forms a complex inside the capsid with the RNA and P-Protein and synthesizes the (-)DNA strand. It constructs a complementary DNA strand using the (-) strand. - RNA is degraded - Nucleocapsid is enclosed as it exits the cell. The extention of the (+) strand stops immediately as the virus leaves the cell
- HBV assembly - a capsid is assembled - capsid acquires a pregenome RNA bound to P protein - Reverse transcription of pregenome RNA by P protein - either goes back to the nucleus or to the rER
- Anzeige
- Factors contributing to HCC HBV:- HBx (viral protein)- responsible for change in histone structure and HCC HCV:- genes promoting cell survival and proliferation
- Hepatitis C virus - Flavivirus, (+)RNA - 6 genotypes (Europe mainly 1) - Transmission: Drug use, sexual, transfusion (before screening) - acute and chronic phase75-85% develop chronic infection! (much more than in HBV) - Receptor-mediated endocytosis: CD81, NPC1L1 - Replication in the cytoplasm: requires liver-specific miR-122 for replication - HCV replication and assembly occurs at lipid droplets associated with ER membrane - Coassembly and secretion with VLDL
- Paramyxoviruses (-)RNA, nonsegmented - Enveloped viruses - mumps virus, measles virus, RSV, Parainfluenzavirus two surface proteins: 1. the attachment protein H/HN/G (measles: H) 2. the fusion protein F - fusion at the plasma membrane (Activation of F protein by Furin protease) - replicate exclusively in the cytoplasm
- Measles virus - spread: aerosol droplets - Primary replication: immune cells, lymphatic organs - Symptoms (10-12 days pi): fever (for 2-4 days), cough, running nose, red watery eyes; rash (for 5-6 days) starts with face and head, spreads through torso, hands and feet (Koplik spots) - Transmission: 4 days before and after rash 1. uses immune cells as ferries to bypass the epithelial barrier2. replicates vigorously in the immune system, including the lymph nodes located near the trachea 3. Site-directed host escape through the trachea-specific receptor protein Nectin-4
- Nectin-4 - adherens junction protein of the immunoglobulin superfamily - interacts with the viral attachment protein (H) - It sustains measles virus entry lateral spread in airway epithelial sheets infected basolaterally via immune cells
- Measles virus receptors 1. Membrane cofactor protein (MCP, CD46)- Receptor for the measles virus vaccine strain - ubiquitously expressed 2. Signaling lymphocyte activation protein (SLAM, CD150)- Receptor for all wild type and the vaccine strains (binds H protein)- Expressed on cells of the immune system 3. Epithelial cell receptor (Nectin 4)- Receptor for all wild type strains - Expressed on cells of lung and bladder epithelia
- Measles virus vaccine - Measles vaccine is generally given between 9 and 15 months of age - Seroconversion at 9 months is about 85% and at 12 months is about 95% - At younger ages seroconversion is hampered by the presence of maternal antibody and the immaturity of the immune system. - second dose recommended
- Subacute sclerosing panencephalitis (SSPE) - chronic encephalitis occurring after infection with measles virus - prevalence varies depending on uptake of measles vaccination - measles virus in the CNS is clonal, implying that virus entered the brain at one time and then gradually spread throughout the nervous system. - During the chronic phase MV accumulates numerous mutations in its proteins, in particular mutations in F, M, and H are believed to contibute to SSPE - clinical manifestations 6 years after infection - treatment with interferon, ribavirin, and isoprinosine - very high lethality
- Clinical stages of SSPE = Subacute sclerosing panencephalitis Stage I Personality changes, failure in school, strange behaviour Stage II Massive, repetitive, and frequent myoclonic jerks, seizures and dementia Stage III Rigidity, extrapyramidal symptoms, and progressive unresponsiveness Stage IV Coma, vegetative state, autonomic failure, and akinetic mutism - periventricular white matter hyperintensities- SSPE inclusion bodies