Transcript Slide 1
Fe A. Bartolome, MD Department of Microbiology Our Lady of Fatima University HEPATITIS A • infectious hepatitis; Enterovirus 72 • Picornavirus genus Heparnavirus/Hepatovirus • naked, icosahedral symmetry • positive sense, ssRNA virus • with a VPg protein attached to 5” end • replication similar to other Picornaviruses • not cytolytic • released by exocytosis HEPATITIS A Characteristics: Stable to: acid (pH 1), solvents (ether, chloroform), detergents, salt/ground water, drying, temperature (40C – 560C) Inactivated by: chlorine treatment, formalin, UV radiation HEPATITIS A Pathogenesis: MOT: fecal-oral food (shellfish – clams, oysters, mussels); water; dirty hands Ingestion oropharynx or epithelial lining of intestines blood stream liver (hepatocytes and Kupffer cells) bile stool Virus shedding: 2-3 wks before & 1 week after onset of jaundice or until antibody is detected Interferon – limits viral shedding NK cells & cytotoxic T cells lysis of infected cells Antibody, complement, ADCC induce immunopathology HEPATITIS A Pathogenesis: MOT: fecal-oral food (shellfish – clams, oysters, mussels); water; dirty hands Ingestion oropharynx or epithelial lining of intestines blood stream liver (hepatocytes and Kupffer cells) bile stool Virus shedding: 2-3 wks before & 1 week after onset of jaundice or until antibody is detected Interferon – limits viral shedding NK cells & cytotoxic T cells lysis of infected cells Antibody, complement, ADCC induce immunopathology HEPATITIS A Epidemiology: 90% of infected children & 20-25% of infected adults with inapparent but productive infections HAV viremia transient blood-borne transmission rare HEPATITIS A Clinical Syndromes: Children: mild infection, usually asymptomatic Adults: abrupt onset of symptoms viral shedding precedes onset of symptoms complete recovery in 99% fulminant hepatitis: 1-3 persons/1000 with 80% mortality immune complex-related symptoms rare HEPATITIS A Laboratory Diagnosis: ELISA or radioimmunoassay (+) IgM anti-HAV acute infection fecal shedding decreases as IgM titer increases (+) IgG anti-HAV resolution, past infection Prophylaxis: immune serum globulin < 2 wks after exposure HEPATITIS B serum hepatitis Hepadnavirus infects liver, kidneys and pancreas humans and chimpanzees 15% of population infected during birth or childhood small, enveloped circular, partly ds DNA virus mature virion Dane particle HEPATITIS B Important proteins: 1. DNA polymerase – with reverse transcriptase & ribonuclease H activity 2. HBcAg – core antigen; surrounds polymerase; T cell antigens 3. HBeAg – minor component of virion; primarily secreted into serum 4. HBsAg – surface antigen; Australia antigen 5. HBx – transcriptional transactivator; promote viral replication; protein kinase HEPATITIS B HBsAg with 3 glycoproteins encoded by same gene but translated from different AUG start codons 1. S (gp27) – contained in M glycoprotein; major component of HBsAg 2. M (gp36) – contained in the L glycoprotein 3. L (gp42) – essential for virion assembly HEPATITIS B Replication unique: 1. With distinctly defined tropism for liver 2. Small genome economy in transcription and translation 3. Replicates through an RNA intermediate Binds to human serum albumin target the virus to the liver Cell penetration partial DNA strand converted to complete dsDNA nucleus HEPATITIS B two phases of hepatocyte infection: 1. Proliferative phase HBV DNA present in episomal form Viral HBsAg & HBcAg + MHC class I molecules activation of CD8+ T cells (+) hepatocyte destruction 2. Integrative phase For hepatocytes not destroyed by immune system viral DNA incorporated into host genome HEPATITIS B (+) HBsAg and HBeAg in blood on-going active infection MOT: 1. Blood & other body fluids – semen, saliva, milk, vaginal secretions, amniotic fluid 2. Sexual contact 3. Perinatal – passage through birth canal Intracellular accumulation of filamentous forms of HBsAg responsible for characteristic ground glass cytopathology HEPATITIS B CMI + inflammation responsible for causing symptoms; eliminate infected hepatocytes Immune complexes between HBsAg and antiHBs (+) type III HS reaction vasculitis, arthralgia, rash, renal damage Infants & young children immarture CMI less ability to resolve infection 90% chronic carriers HEPATITIS B Spread of Hepatitis B Ab HBsAg Immune complex Type III HS Symptoms, resolution Liver Viremia CMI Prevent spread & disease Ab MOT Blood HEPATITIS B Clinical outcomes: Acute Hepatitis B 90% 9% Resolution 1% Fulminant HBsAg+ > 6 months 50% Resolution Asymptomatic carrier state Chronic persistent hepatitis Extrahepatic disease: PAN, GN Chronic active hepatitis Cirrhosis HCC HEPATITIS B Laboratory: Detection of HBeAg is the best correlate to the presence of infectious virus Chronic infection continued finding of HBeAg, HBsAg or both without detectable antibodies HEPATITIS B Interpretation of Serologic Markers of HBV Infection Serologic reactivity Presymptoms Early Acute Acute Anti-HBc Anti-HBe Anti-HBs HBeAg HBsAg Infectious virus + + + + + + + + Chronic Late acute Resolved Vaccinated + + + + +/+/+ + + +/+ - + - HEPATITIS C NANB post-transfusion hepatitis Flavivirus genus Hepacivirus Enveloped, ss positive sense RNA virus 5’ end encodes nucleocapsid core protein highly conserved Envelope proteins E1 and E2 Hypervariable regions (HVR1 & 2) present in E2 sequence Non-structural proteins (e.g. NS5B viral RNAdependent RNA polymerase) with poor fidelity HEPATITIS C Infects only humans and chimpanzees Binds to cells with CD81 surface receptors OR coats itself with LDL or VLDL & uses their receptors for uptake into hepatocytes Inhibit apoptosis & IFN- by binding to TNFR and protein kinase R (PKR) prevent death of host cell and promote persistent infection CMI production of tissue damage Antibody not protective HEPATITIS C Remains cell-associated MOT: 1. Parenteral - >90% of HIV (+) individuals infected with HCV 2. Secretions 3. Sexual 4. Perinatal (6%) PERSISTENT INFECTION AND CHRONIC HEPATITIS ARE THE HALLMARKS! HEPATITIS C Outcomes: HCV Acute infection Recovery & clearance Persistent infection Chronic hepatitis Liver failure Cirrhosis HCC HEPATITIS C Laboratory: (+) anti-HCV antibodies (50-70%) in symptomatic acute infection HCV RNA persists despite presence of neutralizing antibodies (90%) Episodic elevation of serum aminotransferases Treatment: IFN- alone or with ribavirin – only known treatment HEPATITIS D Delta hepatitis; viroid-like Replication defective viral parasite Enveloped, circular RNA virus surrounded by delta antigen core surrounded by HBsAg-containing envelope Unusual transcription and replication process Host cell RNA pol II makes RNA copy replicates genome makes mRNA form a ribozyme cleave RNA circle form mRNA HEPATITIS D MOT similar to HBV Replicate and cause disease only in people with active HBV infection results in cytotoxicity and liver damage With direct cytopathic effect HEPATITIS D Clinical outcomes: Co-infection HDV + HBV Healthy individual 3-4% Fulminant hepatitis Death 90% Recovery w/ immunity rare Chronic HBV/HDV hepatitis Cirrhosis HEPATITIS D Clinical outcomes: Superinfection HDV HBV carrier 7-10% Fulminant hepatitis Death 10-15% 80% Acute, severe disease Chronic HBV/HDV hepatitis Recovery Cirrhosis HEPATITIS E Enteric or epidemic NANB hepatitis MOT: fecal-oral Resembles Calicivirus or Norwalk agent in size and structure non-enveloped, ssRNA virus Symptoms and course similar to HAV Causes only acute disease Poor response to serum IgG Infection serious in pregnant women mortality approx. 20% HEPATITIS G Flavivirus similar to HCV MOT: contaminated blood or blood products; possibly sexual In 75% of infection HGV cleared from plasma; 25% become chronic Site of replication: mononuclear cells not hepatotropic Does not cause elevation in serum aminotransferases With protective effect on patients co-infected with HIV inhibit HIV replication in cultures of peripheral blood mononuclear cells