Bohomolets Microbiology Lecture #16

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  • When certain viruses infect the liver, they cause hepatitis, an inflammatory disease marked by necrosis of hepatocytes and a mononuclear response that swells and disrupts the liver architecture.
  • Many viruses cause hepatitis. Of these, 5 are commonly described as “hepatitis viruses”: HAV; HBV; non-A, non-B viruses, of which HCV is the most common; HDV – delta agent; and HEV.
  • Viral hepatitis is a cause of considerable morbidity and mortality in the human population, both from acute infection and chronic sequel which include, in the case of hepatitis B, C and D, chronic active hepatitis and cirrhosis.
  • The picture show us the most damaged by virus Hepatitis A regions.
  • HAV is also known as enterovirus 72.
  • Humans are the reservoir for HAV. HAV is transmitted by the fecal-oral route. Therefore children are the most frequently infected group. Common-source outbreaks arise from fecally contaminated water or food such as oysters grown in polluted water and eaten raw.
  • As for pathogenesis, the virus probably replicates in the gastrointestinal tract and spreads to the liver via the blood. Hepatocytes are infected. But the mechanism by which cell damage occurs is unclear. HAV infection of cultured cells produces no cytopathic effect. It is likely that attack by cytotoxic T-cells causes the damage to the hepatocytes. The infection is cleared, the damage is repaired, and no chronic infection ensues.
  • Decrease of cases of hepatitis A after beginning of vaccination program is evidence anti-hepatitis A vaccine effectiveness
  • HAV is also known as enterovirus 72.
  • Spherical and filamentous particles don’t contain DNA, they consist only of HBsAg
  • HBsAg is responsible for the ability of the virus to infect its hosts
  • mRNA not only functions in protein synthesis but also is the template for the minus strand of the progeny DNA (during 9-th event)
  • Many HBV infections are asymptomatic and are detected only by the presence of antibody to HBsAg. After entering the blood, the viruses infects hepatocytes, causing necrosis and inflammation. Immune attack against viral antigens on infected hepatocytes is mediated by cytotoxic T cells. The pathogenesis of hepatitis B is probably the result of this cell-mediated immune injury, because HBV does not cause a cytopathic effect. Ag-Ab complexes cause some of the early symptoms, eg, arthralgias, other. Unlike hepatitis A patients, about 10% of patients with hepatitis B become chronic carriers of HBV. A chronic carrier is someone who has HBsAg persisting in their blood for at least 6 months. HBV DNA exists primarily as an episome in the cytoplasm of persistantly infected cells; a small number of copies of HBV DNA are integrated into cell chromosome.
  • When viruses infect the liver, they cause necrosis of hepatocytes. The pathologic change interferes with the liver’s excretion of bile pigments such as bilirubin into the intestine. When bilirubin, a greenish-yellow pigment, accumulates in the blood and tissues, it causes jaundice, a yellow tinge in the skin and eyes.
  • Hepatocellular carcinoma which is one of the ten most common cancers worldwide, is closely associated with hepatitis B, and at least in some regions of the world with hepatitis C virus. A high rate of hepatocellular carcinoma occurs in chronic carriers. Lifelong immuniti is mediated by humoral antibody against HBsAg.
  • Testing procedure fall into 2 categories: detection of different viral Ag and antiviral Ab
  • There is a period of several weeks when HBsAg has disappeared but HBsAb is not yet detectable. This is the “window phase”.
  • Delta hepatitis virus has a worldwide distribution, with relatively high frequency in Italy, the Middle East, Africa and South America.
  • Because HDV can replicate only in cells also infected with HBV, Hepatitis delta can occur only in a person infected with HBV. A person cal either be infected with both HDV and HBV at the same time, be “coinfected” Or be previously infected with HBV and then “superinfected” with HDV. Hepatitis in patient coinfected with HDV and HBV is more severe that in those infected with HBV alone. There is some evidence that delta virus is cytopathic for hepatocytes.
  • Hepatitis in chronic carriers of HBV who become superinfected with HDV is much more severe, and the incidence of fulminant, life-threatening hepatitis, chronic hepatitis, and liver failure is significantly higher.
  • Testing procedure fall into 2 categories: detection of different viral Ag and antiviral Ab
  • Incubation period is 8 weeks. HCV infects hepatocytes primarily, but there is no evidence for a virus-induced cytopathic effect on the liver cells. HCV infection strobgly predisposes to hepatocellular carcinoma. Antibodies against HCV are made, but perhaps as many as half of patients are chronically infected and continue to produce virus for at least a year. Chronic active hapatitis and cirrhosis occur in approximately 10% of these patients.
  • Bohomolets Microbiology Lecture #16

    1. 1. Viral hepatitis
    2. 2. Changes in liver in patients with hepatitis Cirrhosis Hepatocellular carcinoma Local destruction in hepatocytes Norm Fibrose
    3. 3. General features of viral hepatitis <ul><li>Viruses of hepatitis affect only humans ( anthroponosis ) </li></ul><ul><li>Routs of transmission – parenteral and ans fecal-oral route </li></ul><ul><li>All agents are viruses that quite resistant in environment </li></ul><ul><li>Main organ-goal is liver ( hepatocytes) </li></ul><ul><li>Main pathogenic mechanism is immunodependent damage of hepatocytes </li></ul><ul><li>Similar development of disease and clinical symptoms (jaundice ) </li></ul><ul><li>After infection type-specific immunity is developed </li></ul><ul><li>Chronic carriers and complication with cirrhosis and hepatocellular carcinona are possible </li></ul><ul><li>Genetic changeableness is common for most of hepatitis viral agents </li></ul>
    4. 4. Spreading of viral hepatitis
    5. 5. Incidence graphs for hepatitis
    6. 6. Obligate hepatotropic viruses ss – single-stranded ds – double-stranded l- linear c – circular Nonenveloped ssc DNA Cirkoviridae SENV Nonenveloped ssc DNA Parvoviridae TTV Enveloped ssl RNA + Flaviviridae HGV Nonenveloped ssl RNA + Caliciviridae HEV Enveloped ssc RNA - Deltavirus HDV Enveloped ssl RNA + Flaviviridae HCV Enveloped частково длц DNA Hepadnaviridae HBV Nonenveloped ssl RNA + Picornaviridae HAV Structure Genome Family Virus
    7. 7. Geographic distribution of Hepatitis A virus infection
    8. 8. Hepatitis A virus (Hepatovirus) <ul><li>Family Picornaviridae, genus Hepatovirus </li></ul><ul><li>Nonenveloped viruses with cubical type of symmetry </li></ul><ul><li>Small - diameter 20-30 nm </li></ul><ul><li>Genome – single-stranded linear RNA </li></ul><ul><li>RNA has positive polarity </li></ul><ul><li>It has one serotype </li></ul><ul><li>HAV has a replicative cycle similar to that of enteroviruses (Family Picornaviridae) </li></ul><ul><li>HAV disease is far milder, shorter-term, and less virulent than the other forms of hepatitis </li></ul>
    9. 9. Structure of HAV 5’ end of RNA has a protein that serves as a primer for transcription by RNA polymerase
    10. 10. Hepatitis A rate, by age and gender (United States, 1990) Transmission – fecal-oral route.
    11. 11. Hepatitis A rate, by age and gender (United States, 2001)
    12. 12. Events in hepatitis A virus infection
    13. 13. Concentration of Hepatitis A virus in various body fluids
    14. 14. Treatment and prevention of hepatitis A <ul><li>Treatment. N o antiviral therapy is available </li></ul><ul><li>Prevention : </li></ul><ul><ul><li>Active immunization with a vaccine containing hepatitis A viruses that are inactivated by formalin </li></ul></ul><ul><ul><li>Passive immunization with immune serum globulin prior to infection or early in the incubation period for prevent or mitigate the disease </li></ul></ul>
    15. 16. Geographic distribution of Hepatitis B virus infection High Intermediate Low
    16. 17. Electron micrograph of Hepatitis B viruses
    17. 18. Hepatitis B virus <ul><li>Family Hepadnaviridae </li></ul><ul><li>Small - diameter 42 nm </li></ul><ul><li>HBV virion also is named a Dane particle </li></ul><ul><li>Nucleocapsid has cubical type of symmetry </li></ul><ul><li>Enveloped viruses </li></ul><ul><li>The envelope contains a protein called the surface antigen ( HBsAg ) </li></ul><ul><li>Genome – partially double-stranded circular DNA </li></ul><ul><li>Nucleocapsid contains DNA-dependent DNA polymerase </li></ul><ul><li>HBV cannot be cultivated in vitro </li></ul><ul><li>Humans are the only natural hosts of HBV </li></ul>
    18. 19. Some members of hepadnaviridae family infect certain rodents and ducks (but not HBV)
    19. 20. Three different types of a prticles <ul><li>42-nm virions </li></ul><ul><li>22-nm spheres </li></ul><ul><li>Filamentous 22 nm wide and approximately 200 nm long </li></ul>
    20. 21. Electron micrograph of different types of HBV
    21. 22. Structure of HBV particles
    22. 23. HBV antigens HBsAg - hepatitis B surface antigen HBcAg – hepatitis B core antigen HBeAg –hepatitis B e antigen
    23. 24. Nucleic acid of HBV
    24. 25. Events during reproduction of HBV (1) Adherence with viral HBsAg
    25. 26. Events during reproduction of HBV (2) Some of the formed double-stranded closed-circular DNA integrates into the hepatocyte DNA (provirus)
    26. 27. Events during reproduction of HBV (3) HBs
    27. 28. The three main modes of transmission of hepatitis B <ul><li>During sexual intercourse </li></ul><ul><li>Perinatally from mother to newborn </li></ul><ul><li>Via blood </li></ul>
    28. 31. The clinical features of hepatitis B
    29. 32. Man with jaundice caused by HBV
    30. 33. Hepatocellular carcinoma (hepatoma) associated with HBV-infection
    31. 34. Laboratory diagnosis of hepatitis B <ul><li>Immunoassay for HBsAg is used for detection of early acute HBV infection ( immunofluorescence assay ELISA or radioimmunoassay ). HBsAg disappears from the blood after 24 weeks. </li></ul><ul><li>In 2 weeks after HBsAg, HBcAb (antibody to HBcAg) appears in blood and is always positive and can be used to make the diagnosis ( immunoassay ) </li></ul><ul><li>Detection of HBsAb (antibody to HBsAg) with immunoassay </li></ul><ul><li>Detection of viral DNA with PCR </li></ul>
    32. 35. Window period
    33. 37. Serologic test results in four stages of HBV infection Positive Positive Positive Positive HBcAb Negative Positive Negative Negative HBsAb Positive Negative Negative Positive HBsAg Chronic carries state Complete recovery Window phase Acute disease Test
    34. 38. Treatment and prevention <ul><li>Treatment . Alpha interferon is clinically useful for treatment of chronic hepatitis B </li></ul><ul><li>Prevention : </li></ul><ul><ul><li>Active immunization with vaccine: </li></ul></ul><ul><ul><ul><li>Modern vaccine contains HBsAg produced in yeasts by genetic engineering techniques </li></ul></ul></ul><ul><ul><ul><li>Prior vaccine is inactivated vaccine consisting of HBsAg prepared from spherical particles purified from the serum of infected individuals. </li></ul></ul></ul><ul><ul><li>Passive immunization with hepatitis B immune globulin contains HBsAb (it is prepared from sera of patients who have recovered from hepatitis B </li></ul></ul>
    35. 39. Geographic distribution of HDV infection
    36. 40. Hepatitis D virus (delta agent) <ul><li>Delta hepatitis virus is a defective virus </li></ul><ul><li>Can not replicate by itself, because it does not have the genes for its protein coat </li></ul><ul><li>HDV can replicate only in cells also infected with HBV </li></ul><ul><li>Enveloped virus </li></ul><ul><li>Genome – single-stranded RNA with negative polarity, covalently closed circle. </li></ul><ul><li>The RNA of HDV is very small and encodes only one protein, the internal core protein called delta antigen </li></ul>
    37. 41. Structure of HDV HDV uses the surface antigen of HBV (HBsAg) as a coat
    38. 42. HDV is transmitted by the same means as is HBV <ul><li>Sexually </li></ul><ul><li>Perinatally </li></ul><ul><li>By blood </li></ul>
    39. 43. HBV-HDV coinfection
    40. 44. HBV-HDV superinfection
    41. 45. Laboratory diagnosis of hepatitis D <ul><li>Detection of delta antigen with immunoassay </li></ul><ul><li>Detection of IgM antibody to delta Ag </li></ul><ul><li>No specific antiviral therapy </li></ul><ul><li>No vaccine against HDV </li></ul>
    42. 46. Geographic distribution of HCV infection
    43. 47. Hepatitis C virus <ul><li>Family Flaviviridae </li></ul><ul><li>Enveloped virus </li></ul><ul><li>Nucpeocapsid with cubical type of symmetry </li></ul><ul><li>Genome – single-stranded, positive polarity RNA </li></ul><ul><li>No virion polymerase </li></ul><ul><li>Multiple serotypes exist, the gene encoding the envelope glycoprotein has hypervariable regions </li></ul><ul><li>HCV has not grown in cell culture </li></ul>
    44. 48. Structure of hepatitis C virus
    45. 49. HCV is transmitted by the same means as is HBV <ul><li>Sexually </li></ul><ul><li>From mother to child </li></ul><ul><li>Via blood </li></ul>
    46. 53. Laboratory diagnosis of hepatitis C <ul><li>Detection of antibodies to HCV in an ELISA </li></ul><ul><li>Detection of viral RNA in PCR </li></ul><ul><li>Alpha interferon is used for the treatment of chronic hepatitis C </li></ul><ul><li>There is no vaccine against HCV, and immunoglobulins are not available </li></ul>
    47. 55. Geographic distribution of HEV infection
    48. 56. Hepatitis E virus <ul><li>Family Caliciviridae </li></ul><ul><li>Small, nonenveloped virus </li></ul><ul><li>Genome – single-stranded RNA </li></ul><ul><li>Transmission by fecal-oral rout </li></ul><ul><li>Clinically the disease resembles hepatitis A </li></ul><ul><li>Chronic liver disease does not occur </li></ul><ul><li>Diagnosis is typically made by excluding HAV and other causes </li></ul><ul><li>There is no antiviral treatment and no vaccine </li></ul>
    49. 57. Clinical features of hepatitis viruses No None No ? Fecal-oral HEV No Ab to delta Ag. RNA Yes With coin-fection, same as HBV Parenteral HDV No HCV Ab. RNA Yes 5-9 weeks Parenteral HCV Yes HBsAg, HBsAb, IgM HBcAb. DNA Yes 10-15 weeks Parenteral HBV Yes IgM HAV. RNA No 3-5 weeks Fecal-oral HAV Vaccine Laboratory diagnosis ( immunoassay, PCR ) Chronic carriers Incuba-tion period Mode of transmission Virus

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