Nonenveloped DNA Viruses (Parvoviridae, Adenoviridae, Papovaviridae) PDF

Nonenveloped DNA viruses (Parvoviridae, Adenoviridae) Helen Kalandarishvili UG 2023 VIRAL GROUPS DNA VIRUSES EXEPTION...

Nonenveloped DNA viruses (Parvoviridae, Adenoviridae) Helen Kalandarishvili UG 2023 VIRAL GROUPS DNA VIRUSES EXEPTION Replicates in Cytoplasm All are DS Poxviridae All replicate in the nucleus Icosahedral Complex Naked Enveloped 1- Poxviridae Non-Enveloped Ether-Sensitive Ether-Resistant ✓ Parvoviridae ✓ Papillomaviridae Single stranded ✓ Herpesviridae ✓ Polyomaviridae ✓ Hepatnaviridae ✓ Adenoviridae REPLICATION OF DNA VIRUSES DOUBLE-STRANDED DNA VIRUSES (all DNA viruses) They use the host cell DNA- Replicate in the nucleus dependent RNA polymerase to synthesize their mRNA Polyoma virus Adenovirus Papilloma virus  ADENOVIRUSES Viruses were named for the Many adenovirus infections are adenoids, from which they subclinical, and virus may were first isolated in 1953. persist in the host for months. Can replicate and produce disease in the Respiratory Gastrointestinal Urinary tracts and in the eye ADENOVIRUSES The shell is 70 to 90 nm in diameter made up of → 252 An isoschahedral protein shell structural capsomeres surrounding a protein core that contains the linear double- stranded DNA genome The 12 vertices of the icosahedron are occupied by units called pentons, each of which has slender projection called a fiber There is no envelope The hexons, pentons, and fibers are major adenovirus antigens important in viral classification and disease diagnosis ADENOVIRUSES This family contains two genera: ✓ Aviadenovirus – infects birds ✓ Mastadenovirus - infects mammals Human adenovirus antigenic types - HAdV-1 to 57 - have been isolated from humans and from various animals. ✓ 1/3 are responsible for most cases of human adenovirus disease. ✓ A single serotype may cause different clinical diseases ✓ More than one type may cause the same clinical illness Seven species - A to G - on the basis of their physical, chemical, and biologic properties ADENOVIRUSES Certain serotypes are associated with specific Infections with types: syndromes: ✓ 1, 2, 5, 6 - occur during the first years of life ✓ Respiratory types - 1, 2, 3, 4, 5, 7, 21 ✓ 3, 7 - during school years ✓ Gastroenteritis types - 40, 41 ✓ 4, 8, and 19 are not encountered until ✓ Epidemic keratoconjunctivitis – 8, 19 adulthood ✓ Hemorrhagic cystitis – 11, 21 ✓ 12, 18, and 31 induce tumors into newborn hamsters Adenoviruses cause primary infection in children and less commonly in adults. Most infections are mild and self-limited  ADENOVIRUSES Adenoviruses exist in all parts of the world. They are present year-round and usually do not cause community outbreaks of disease. Adenoviruses are spread by: ✓ Direct contact ✓ Fecal-oral route ✓ Respiratory droplets ✓ Contaminated fomites Adenoviruses can remain viable for several weeks on sinks and hand towels, and these may be a source of transmission. ADENOVIRUSES Adsorbed virus is internalized Adenoviruses replicate well into endosomes and move only in epithelial cells rapidly into the cytosol The virus attaches to cells via Replication the fiber structures Microtubules are involved in the transport across the cytoplasm to the nucleus. The host cell receptor is CAR (coxsackie adenovirus receptor), CD46 for the group B human Uncoating commences in the cytoplasm adenovirus serotypes and co- and is completed in the nucleus receptor molecule is αv integrin. ADENOVIRUSES The adenovirus life cycle is separated by the DNA replication process into two phases: Early Phase Late Phase expressing non-structural, focused on producing of structural regulatory proteins. proteins ADENOVIRUSES Alter the expression of host proteins that are Early Phase necessary for DNA synthesis The early genes – expressing non- Activate other virus genes (virus-encoded DNA structural, regulatory proteins. polymerase) More than 20 early proteins, majority Avoid premature death of nonstructural - involved in viral DNA replication, the infected cell by the host- are synthesized in adenovirus-infected cells immune defenses The E1A early gene must be expressed The E1B early region encodes in order for the other early regions to be proteins that block cell death transcribed and modulate the cell cycle ADENOVIRUSES The DNA is replicated by a strand displacement mechanism. There are no Okazaki fragments, both strands are synthesized in a continuous fashion. Early genes for host and viral transcription control, viral DNA replication Late genes for virion structure ADENOVIRUSES Late Phase Once the viral components have successfully been is focused on producing of structural replicated, the virus is assembled into its protein protein to pack all the genetic material shells and released from the cell as a result of virally produced by DNA replication induced cell lysis. The adenovirus infectious cycle takes about 24 hours. Nevertheless, about 100,000 virus particles are produced per cell. The assembly process is inefficient - about 80% of hexon capsomeres and 90% of viral DNA are not used. ADENOVIRUSES marked rounding, enlargement, and aggregation of affected cells into grape-like clusters. Adenoviruses are cytopathic for human cell cultures, particularly primary kidney and epithelial cells. adenovirus infections do not induce syncytia or multinucleated giant cells All adenoviruses can morphologically transform cells infected with cells in culture regardless of their oncogenic some adenovirus potential in vivo types, rounded intranuclear inclusions containing DNA Adenoviruses are not thought to be important in human cancer.  ADENOVIRUSES PATHOGENESIS They usually do not spread Adenoviruses infect and replicate in → beyond the regional lymph Epithelial cells of the respiratory tract nodes. – Eye - Gastrointestinal tract - Urinary bladder - Liver Group C viruses persist as latent Most human adenoviruses replicate in infections for years in adenoids intestinal epithelium after ingestion, but and tonsils and are shed in the usually produce subclinical infections feces for many months after the rather than overt symptoms. initial infection. ADENOVIRUSES RESPIRATORY DISEASES Adenoviruses are responsible for 5% of acute respiratory Symptoms - cough, nasal diseases in infants and young children and much less in adults congestion, fever, and sore throat. Acute febrile pharyngitis (types 1, 3 and 5) Acute respiratory disease syndrome (types 3, 4 and 7) ✓ most commonly seen in infants and young ✓ Cause syndrome among military recruits children ✓ Fever, sore throat, nasal congestion, cough, and ✓ symptoms - cough, stuffy nose, fever, sore malaise, sometimes leading to pneumonia throat Pneumonia (types 3, 7, and 21) ✓ a complication of acute respiratory disease in both children and adults. ✓ responsible for about 10–20% of pneumonias in childhood. ADENOVIRUSES EYE INFECTIONS Transmitted in several ways, but hand-to-eye transfer is particularly important Pharyngoconjunctival fever (type 3,7 and 21) Epidemic keratoconjunctivitis ✓ symptoms are similar to those of acute febrile ✓ Caused by types 8, 19, and 37 pharyngitis, but conjunctivitis is also present ✓ Disease occurs mainly in adults, Highly ✓ Occur in outbreaks, such as at children’s contagious summer camps (“swimming pool ✓ Resolves in 2 weeks but may leave sub epithelial conjunctivitis”) opacities in the cornea for up to 2 years. ✓ Duration is 1–2 weeks ✓ Complete recovery with no lasting sequelae is the common outcome ADENOVIRUSES INFANTIL GASTROENTERITIS GASTROINTESTINAL DISEASE Many Adenoviruses replicate in intestinal Two serotypes (types 40 and 41) associated cells and are present in the stools without 5–15% of cases of viral gastroenteritis in being associated with GIT disease. young children. The enteric adenoviruses are very difficult to cultivate. ADENOVIRUSES OTHER DISEASES Transplant patients Immunocompromised patients Children, especially boys Suffer adenovirus infections, ✓ Liver transplants may ✓ Types 11 and 21 may especially in the gastrointestinal develop adenovirus cause acute hemorrhagic tract hepatitis in the allograft. cystitis ✓ Heart transplants who ✓ Virus commonly occurs in develop myocardial the urine of such adenovirus infections are at patients. increased risk of graft loss ADENOVIRUSES Canine adenoviruses form of adenovirus that is highly infectious in dogs, causes an acute liver infection 2 types are well known CAdV-1 → CAdV-2 → causes infectious canine is one of the potential hepatitis, respiratory and causes of kennel cough eye infections Adenoviruses are also known to cause respiratory infections in→ Core vaccines for dogs include attenuated horses, cattle, pigs, sheep, and goats. live CAdV-2, which produces immunity to CAdV-1 and CAdV-2 ADENOVIRUSES Normal, healthy adults generally have antibodies to several types. Immunity Adenoviruses induce effective and long-lasting immunity against Maternal antibodies usually reinfection protect infants against severe adenovirus respiratory infections. Resistance to clinical disease directly related to the presence of circulating neutralizing antibodies, which probably persist for life. possibly because of infection of regional lymph nodes and lymphoid cells in the Neutralizing antibodies against gastrointestinal tract one or more types have been detected in over 50% of infants 6– 11 months old. But antibodies may not always prevent reinfection ADENOVIRUSES Depending on the clinical disease, virus may be recovered Diagnosis from → stool, urine, throat, conjunctival, or rectal swab. Duration of adenovirus excretion varies among different illnesses: ✓ 1–3 days - throat of adults with common cold ✓ 3–5 days - throat, stool, and eye, for pharyngoconjunctival fever ✓ 2 weeks - eye, for keratoconjunctivitis ✓ 3–6 weeks - throat and stool of children with respiratory illnesses ✓ 2–12 months - urine, throat, and stool of immunocompromised patients. ADENOVIRUSES Diagnosis Primary human embryonic kidney cells are most susceptible Virus isolation in a cell culture requires human cells. human epithelial cell lines ( HEp-2, HeLa, and KB) are sensitive but are difficult to maintain without degeneration for long time The development of characteristic cytopathic effects - rounding and clustering of swollen cells - indicates the presence of adenovirus in inoculated cultures. Immunofluorescence tests - Polymerase chain Isolates can be identified as reaction (PCR) - Electron microscopy – ELISA - Latex adenoviruses by: agglutination tests. ADENOVIRUSES There is no specific treatment for adenovirus infections. Prevention The easiest way to prevent infections: ✓ Careful hand washing ✓ Disinfection of surfaces with sodium hypochlorite ✓ Use of paper towels ✓ Chlorination of swimming pools and waste water. ADENOVIRUSES Host Defence Live non attenuated adenovirus vaccine exist against three types 4, 7 and 21 encased in gelatin-coated capsules and given orally A new live, oral vaccine (introduced in 1971) induces neutralizing against type 4 and type 7 was approved in 2011. antibodies. (military population) After 1999 was no longer available as its manufacture had been discontinued. REPLICATION OF DNA VIRUSES SINGLE-STRANDED DNA VIRUSES (Parvoviruses) They replicate within the nucleus, and form a double- stranded DNA intermediate during replication. Parvoviruse PARVOVIRUSES The genome is single-strand DNA Parvoviruses are the simplest DNA animal viruses. Icosahedral, nonenveloped viruses 18–26 nm in diameter There is no virion polymerase The capsid has icosahedral symmetry stable between pH 3 and 9 Virions are extremely resistant to inactivation: with stand heating at 56 °C for 60 minutes PARVOVIRUSES Two subfamilies Parvovirinae Densovirinae infect vertebrates, Feline panleukopenia infect insects. comprise three virus and canine genera. parvovirus Parvovirus and Erythrovirus Dependovirus - defective viruses are able to replicate and depend on a helper virus (an autonomously in rapidly adenovirus or herpesvirus) for dividing cells. replication. Human parvovirus Human "adeno-associated viruses" B19 - member of the have not been linked with any Erythrovirus genus. disease PARVOVIRUSES Parvovirus B19 The only known parvovirus pathogenic for humans infects primarily two types of cells red blood cell precursors (erythroblasts) endothelial cells in the blood in the bone marrow → aplastic There is one serotype anemia vessels → in part, for the rash associated The B19 virus is widespread. with erythema infectiosum. Infections can occur throughout the year Most commonly seen as outbreaks in schools. Antibody develops between the ages of 5 and 19 years. Up to 60% of all adults and 90% of elderly people are seropositive. Many infections are subclinical. Infection provides lifelong immunity against reinfection. PARVOVIRUSES Parvovirus B19 The parvoviruses are highly dependent on cellular functions for replication B19 virus replicates only when a cell is in S phase ✓ which explains why the virus replicates in red cell precursors but not in mature red cells. ✓ co-infection with other viruses (such as adenovirus or herpesvirus) is essential. The cellular receptor for B19 is blood group P antigen (globoside) P antigen is expressed on → mature erythrocytes, erythroid progenitors, megakaryocytes, endothelial cells, placenta, and fetal liver and heart PARVOVIRUSES Replication After adsorption to host cell receptors, the virion penetrates and moves to the nucleus, where replication occurs. The single-stranded genome DNA has “hairpin” loops at both of its ends that provide double-stranded areas for the cellular DNA polymerase to initiate the synthesis of the progeny genomes.  PARVOVIRUSES The viral mRNA is synthesized by cellular RNA polymerase from the Replication double-stranded DNA intermediate. Newly synthesized single-stranded DNA converted to double-stranded DNA and serve once again as a template for transcription or replication The progeny virions are assembled in the nucleus. it can be encapsidated to form new virions that are released by cell lysis. There are two capsid proteins. Viral replication results in cell death. PARVOVIRUSES ✓ The respiratory route ✓ Parenterally by blood transfusions ✓ Vertically from mother to fetus Transmission is presumably by There is no evidence of virus excretion in feces or urine. Transmission of B19 from patients with aplastic crisis to members of the hospital staff has been documented → ✓ Patients with aplastic crisis are likely to be infectious during the course of their illness ✓ Patients with fifth disease are probably no longer infectious by the time of onset of rash PARVOVIRUSES PARVOVIRUS PATHOGENESIS PARVOVIRUSES Polyarthralgia-arthritis syndrome in normal adults Erythema infectiosum (Slapped Cheek Syndrome, “fifth disease”), a common childhood exanthem Aplastic crisis (Anemia) in Causes patients with hemolytic disorders Fetal death Chronic anemia in immunocompromised individuals PARVOVIRUSES ERYTHEMA INFECTIOSUM (FIFTH DISEASE) Symptoms → Most common in children of early school age mimic rheumatoid arthritis, and the Illness is biphasic → First and Second arthropathy may persist for weeks, months, or years Both sporadic cases and epidemics have been described. (joints in the hands and the knees are most frequently affected.) Incubation period -1–2 weeks Viremia occurs 1 week after infection and persists for about 5 days  PARVOVIRUSES ERYTHEMA INFECTIOSUM (FIFTH DISEASE) first phase second phase end of the first week After 17 days symptoms are flu-like, fever, malaise, an erythematous facial rash, a lace like rash myalgia, chills on the limbs or trunk, joint symptoms detection of circulating IgM-parvovirus Rash fading after 2–4 days immune complexes. The joint symptoms may persist longer. Specific IgG antibodies appear about 15 days post infection. The four other macular or maculopapular rash diseases of childhood are measles, rubella, scarlet fever, and roseola. PARVOVIRUSES POLYARTHRALGIA-ARTHRITIS Virus can cause arthritis mainly involving the small joints of the hands and feet bilaterally, especially in women It resembles rheumatoid arthritis May persist for weeks, months, or years.  PARVOVIRUSES TRANSIENT APLASTIC CRISIS (ANEMIA) An abrupt cessation of red blood cell synthesis in the bone marrow Reduction in the hemoglobin level of peripheral blood. Lower production of red blood cells becomes apparent only in patients with chronic hemolytic anemia People with normal red blood cells do not have clinically apparent anemia, although their red blood cell precursors are infected. Few anemia patients have a rash. Symptoms of transient aplastic crisis occur during the viremic phase of infection. Transient aplastic crisis may occur after bone marrow transplantation. PARVOVIRUSES INFECTION IN IMMUNODEFICIENT PATIENTS B19 may establish persistent infections and cause chronic suppression of bone marrow and chronic anemia in immunocompromised patients. The disease is called → Pure Red Cell Aplasia. The anemia is severe, and patients are dependent on blood transfusions. It has been observed in patient with: ✓ congenital immunodeficiency ✓ malignancies ✓ AIDS ✓ organ transplants PARVOVIRUSES INFECTION DURING PREGNANCY Maternal infection with B19 virus during the first or second trimester of pregnancy (virus may cross the placenta) results in: ✓ hydrops fetalis ✓ fetal death ✓ severe anemia The overall risk of human parvovirus infection during pregnancy is low Fetal loss occurs in less than 10% of primary maternal infections Fetal death occurs most commonly before the 20th week of pregnancy There is no evidence that B19 infection causes physical abnormalities PARVOVIRUSES Diagnosis Both virus-specific IgM and IgG antibodies are made following B19 infections. The rash associated with erythema infectious is at least partly immune complex-mediated. B19 can be found in blood and respiratory secretions of infected patients. PCR - The most sensitive tests detect viral DNA. ✓ in serum, blood cells, tissue samples, respiratory secretions. Detection of B19 IgM antibody; it is present for 2–3 months after infection. The virus is difficult to grow. PARVOVIRUSES Prevention Good hygienic practices, should help prevent the spread of virus Careful hand washing is the easiest way to prevent infection. There is no vaccine against human parvovirus ✓ There are effective vaccines against animal parvoviruses for use in cats, dogs, and pigs. Treatment There is no specific treatment for adenovirus infections. ✓ Fifth disease and transient aplastic crisis are treated symptomatically. ✓ Transient aplastic crisis may require transfusion therapy. Commercial immunoglobulin preparations contain neutralizing antibodies to human parvovirus. ✓ ameliorate persistent B19 infections in immunocompromised patients and in those with anemia. Lecture N3 the END! ADENOVIRUSES