An introduction to Parvoviridae

This power point file is an introduction to Parvoviruses for medical students and related disciplines.

1. 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 1 An Introduction to Parvoviridae

2. The most dependent viruses Latin Parvus = small The smallest of all human viruses(only 20-25 nm in diameter). It might be thought that viruses as a class represent the ultimate in parasitism. Reliant as they are on their host cells to provide most of the machinery or replication. The Parvoviruses, show a still further degree of dependence . As they can replicate only in the presence of active DNA synthesis in rapidly dividing host cells, or under the influence of another virus infection(helper virus). The reason lies in their minute size( smallest of all human viruses ). 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 2

3. Little about it`s small genome Contain so little genetic information. Consist of a single icosahedral shell, surrounding a linear single-stranded DNA molecule of very limited coding potential: 5kb for human parvovirus B19 4.7kb for human dependoviruses 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 3

4. More about it`s small genome The ssDNA genome is of negative polarity! But some virions package a positive strand instead(up to 50% of them in the case of the genus Dependovirus). All genomes display long terminal palindromic sequences enabling each of ends of the molecule to fold back on itself to form a hairpin structure. 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 4

5. Major fact about their replication They are able to replicate only in dividing cells, Or, In the case of members of the Dependovirus genus, in the presence of a helper virus. This requirement for dividing cells accounts for their predilection for: Bone marrow Gut Developing fetus 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 5

6. Parvoviruses of cats, dogs, and mink cause panleukopenia and enteritis. Rat parvovirus causes congenital malformation of the fetus. 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 6

7. Human parvovirus B19 Discovered in the serum of asymptomatic blood donors. Associated with: A very common exanthematous disease of children (Fifth disease) Aplastic crisis (in patients with chronic hemolytic anemia ) Hydrops fetalis 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 7 5 th.

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9. More infections Another human parvovirus cause gastroenteritis 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 9

10. The capsid Composed: One major polypeptide Two minor polypeptides Arranged to form 60 protein subunits. 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 10

11. Some physicochemical properties The virus is very stable, resisting: 60˚C for some hours. Variation from pH 3 to 9 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 11

12. Simple Classification 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 12

13. Parvovirus replication Unlike the double-stranded DNA viruses !! ssDNA parviruses can replicate only in dividing cells. Parvoviruses replicate in the nucleus: Transcription and replication of the genome Accumulation of nonstructural proteins Assembly of virions 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 13

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15. Parvovirus receptor & Co-receptors 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 15

16. Parvovirus replication No enzyme in the virion . 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 16 Cellular DNA polymerase Cellular DdRp II Alternative splicing Nonstructural and structural proteins are encoded by the left and right side of the genome respectively Transactivation vs. down regulation

17. 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 17 Genome replication Palindromic 3` terminal sequence Ds-replicative intermediate form In infected bone marrow cells (concatemers)

18. Parvovirus:Clinical aspect Parvovirus clinical syndromes: Erythema infectiosum(fifth disease) Arthritis (especially in young women) Aplastic crisis in chronic hemolytic anemia Chronic anemia in immunodeficiency syndromes Hydrops fetalis 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 18

19. Clinical aspects 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 19 Over a week few days

20. Clinical aspects Patients displayed a biphasic illness: (day 8-11) Fever, malaise, myalgia, chills, peak level of virus in blood, destruction of erythroblasts in bone marrow. (day 17-24) rash and arthralgia occurred, viremia had disappeared, IgM had peaked, IgG had begun to rise. 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 20

21. Erythema infectiosum Fifth disease Innocuous contagious exanthema of childhood. Erythematous rubella-like rash on face flushed cheeks Though fleeting: rash may reappear in weeks /months. Arthralgia: Children: occasionally Adult: regular Especially in women: peripheral joints: hands, wrists, knees, ankles. Polyarthritis is often the dominant feature 20-25% of infections are asymptomatic. 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 21 Limbs Trunk Fades rapidly in 1-2 day, a fine lace

22. 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 22 The pathogenesis of erythema infectiosum is probably a result of antibody-antigen immune complex depositions in skin , blood vessels and synovia. The rash typically appears on the cheeks followed by a lace-like maculopapular rash on the upper part of the body. Joint symptoms are more common in adults than in children. In addition to deposition of immune complexes, the inflammatory response in synovial tissue may be a result of the secreted phospholipase A2 motif in the unique region of the B19 minor capsid protein .

23. Transient Aplastic Crisis(anemia) Temporary, potentially life-threatening complication in: Chronic hemolytic anemia: Sickle cell anemia Thalassemia Hereditary spherocytosis Characteristics of severe anemia: Pallor, weakness, lethargy Recovery occurs spontaneously in a week. Blood transfusion is sometimes lifesaving. 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 23 Infected with Parvovirus B19 Usually no rash Sudden drop in hemoglobin Total disappearance of erythrocytes precursors from bone marrow Reticulocytes from the blood

24. 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 24 B19 binds to immature erythroblasts thereby arresting production of mature erythropoietic cells. Following acute infection, the reticulocyte count in peripheral blood is zero and if the patients have an underlying disorder with pathologic red cell survival, the number of erythrocytes may fall dramatically in peripheral blood. The pathogenesis of thrombocytopenia is thought to be explained by the cytotoxicity of the NS1 protein .

25. Parvovirus B19: other complications Chronic anemia in immunodeficient patients in: Acute leukemia on chemotherapy AIDS patients Bone marrow recipient transplant Children with congenital immune deficiency state. Hydrops fetalis: general edema : Severe anemia Congestive cardiac failure 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 25 Dying of fetuses

26. Parvovirus in pregnancy 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 26 Vertical transmission of B19 from a primary infected mother may cause fetal infection. Pathogenic mechanisms include development of acute anemia upon infection of fetal hematopoietic cells. In early pregnancy hematopoiesis is seen in the liver and in later pregnancy this shifts to the bone marrow. The anemia may resolve spontaneously or proceed by causing cardiac failure and development of hydrops fetalis and in rare cases fetal death. The virus may also cause myocarditis and heart arrest by direct infection of myocardial tissue. Modified from Anderson and Young .

27. Clinical complications associated with B19 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 27

28. Epidemiology Ubiquitous, common, highly contagious. Year-round infection, spring epidemics among school-children 4-10 years. Readily transmitted by: Respiratory secretions & close contacts During the incubation period of erythema infectiosum Chron.hemo . Anem . Patients are infectious up to 1 week after aplastic crisis. B19 in immunocompromised patients: excrete virus for months/years. Transplacental transmission: Less than 10% leads to fetal death. Rarely congenital malformations Blood transfusion: Factor VIII is a great problem 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 28 Attack rate:25 – 50% Rash appearance: no more infectious 30% maternal infections transmit into fetus Usually no harm! The virus is heat stable: survive in clotting factor concentrate

29. Treatment and control Erythema infectiosum requires no treatment. Aplastic crisis requires supportive care and blood transfusion. Severe persistent anemia( Immunocomp . Patients) requires IVIG. Persons of potential risk: Pregnant non-immune women Immunocompromised individuals Chronic hemolytic anemia 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 29

30. B19 in different risk groups 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 30

31. Dependoviruses Adeno-associated viruses 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 31

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33. Laboratory diagnosis Cell culture : bone marrow, fetal lever (with erythropoietin & IL-3). MB-02( H.megakaryocytic leukemia cell line)(with GM-CSF). Serology : EIA/RIA: IgM or significant rise of IgG. Molecular detection: Detection of virus DNA by: Nucleic acid hybridization PCR EIA: for viral antigens EIA Electron microscopy: Nuclear inclusion bodies: crystalline array of virions in nucleus. 2/19/2016 Dr. Kaveh Haratian, Dept. of Microbiology and Immunology, ABZUMS 33 Antigen produced by molecular cloning In hydrops fetalis: in situ hybridization

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