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Adenovirus.micro Adenovirus.micro Presentation Transcript

  • ADENOVIRUS Maria Ellery M. Mendez, MD, DPASMAP, FPAMS, FPAAAMI Department of Microbiology Our Lady of Fatima University
  • PROPERTIES
    • Virion :
      • Non-enveloped; icosahedral, 70 – 90 nm in diameter, 252 capsomeres (12 vertices or penton bases + 240 hexon capsomeres); fiber projects from each vertex
  • PROPERTIES
    • Composition :
      • DNA (13%), protein (87%)
    • Genome :
      • Linear, double stranded DNA, 26 – 45 kbp, protein-bound to termini, infectious
  • PROPERTIES
    • Proteins :
      • 11 virion proteins
      • Hexon & penton capsomeres are the major components on the surface of the virus particle
      • Penton base with toxin-like activity
      • Fibers – with type-specific antigens; associated with hemagglutinating activity
  • PROPERTIES
    • Classification:
      • Aviadenovirus (birds) and Mastadenovirus (mammals)
      • Human adenovirus: six groups (A to F)
    • Replication :
      • Nucleus; only in cells of epithelial origin
      • Attaches to cells via the fiber structures
      • Host cell receptor: CAR (coxsackie-adenovirus receptor)  member of immunoglobulin gene superfamily
  • PROPERTIES
    • Replication : Early Events
      • Induce the host cell to enter the S phase of the cell cycle  create conditions conducive to viral replication
    Virus attachment (adsorption) Interaction of penton base with cellular integrins Virus internalization into endosomes CYTOSOL Uncoating NUCLEUS
  • PROPERTIES
    • Replication : DNA Replication & Late Events
      • Takes place in the nucleus
      • Late events begin concomitantly with the onset of viral DNA synthesis
      • Host genes continue to be transcribed in the nucleus late in the course of infection
  • PROPERTIES
    • Virus Effects on Host Defense Mechanisms
      • VA RNAs: prevent activation of an interferon-inducible kinase that inactivates eukaryotic initiation factor 2
      • E3 region proteins: inhibit cytolysis of infected cells by host responses
        • E3 gp19-kDa protein: blocks movement of MHC class I antigen to the cell surface  protect from CTL-mediated lysis
        • Other E3-encoded proteins: block TNF- 
  • PROPERTIES
    • Virus Effects on Cells
      • Oncogenes: E1A (pRB) and E1B (p53) – animals such as hamsters
      • Cytopathic for human cell cultures, particularly primary kidney and continuous epithelial cells
      • CPE: marked rounding, enlargement, and aggregation of affected cells into grape-like clusters without lysis of infected cells
  • PROPERTIES
    • Immunity
      • Induce effective and long-lasting immunity against re-infection
      • Resistance to clinical disease directly related to presence of circulating neutralizing antibodies – persist for life
      • Type-specific neutralizing antibodies do not always prevent re-infection
      • Group-specific antibodies not protective and decline with time
      • Maternal antibodies protective for infants against severe respiratory infections
  • PATHOGENESIS
      • Infect and replicate in epithelial cells of the respiratory tract, eye, GIT, urinary bladder, and liver
      • Usually do not spread beyond the regional LN
      • Group C viruses persist as latent infections in adenoids and tonsils  shed in the feces for many months
      • Most human adenoviruses replicate in intestinal epithelium after ingestion
  • EPIDEMIOLOGY
    • Usually do not cause outbreaks of disease
    • Most common serotypes in clinical samples: low numbered respiratory types ( 1, 2, 3, 5, 7 ) and the gastroenteritis types ( 40 and 41 )
    • MOT: direct contact, fecal-oral route, respiratory droplets, or contaminated fomites
    • Infections with types 1,2,5, and 6 – chiefly during first year of life
    • Infection with types 3 and 7 – school years
    • Infection with types 4,8 and 19 – adulthood
    • Types 34 and 35 – bone marrow and renal transplant recipients
  • CLINICAL FINDINGS
    • RESPIRATORY DISEASES
      • Cough, nasal congestion, fever, and sore throat  most common in infants and children; usually involving Group C viruses
      • Types 3, 7, and 21: pneumonia (10-20%) in childhood
      • Types 4 and 7 (and occ. Type 3): acute respiratory disease among military recruits; occurs in epidemic form
  • CLINICAL FINDINGS
    • EYE INFECTIONS
      • Pharyngoconjunctival fever
        • Occur in outbreaks, such as at children’s summer camps (“ swimming pool conjunctivitis ”); associated with types 3 & 7
      • Epidemic keratoconjunctivitis
        • More serious; types 8, 19 and 37
        • Adults; highly contagious
        • MOT: fomites (e.g. sinks, hand towels)
        • Acute conjunctivitis  keratitis
  • CLINICAL FINDINGS EYE INFECTIONS
  • CLINICAL FINDINGS
    • GASTROINTESTINAL DISEASE
    • Types 40 and 41
      • Associated with infantile gastroenteritis
      • Account for 5-15% of viral gastroenteritis in young children
      • Abundantly present in diarrheal stools
  • CLINICAL FINDINGS
    • OTHER DISEASES
    • Types 11 and 21
      • Acute hemorrhagic cystitis in children, especially boys; (+) virus in urine
    • Types 1 – 7
      • Respiratory disease progressing to severe pneumonia in transplant patients
      • Children with liver transplants – hepatitis
      • Children with heart transplants – inc. risk of graft loss
  • LABORATORY DIAGNOSIS
    • SAMPLES should be collected from affected sites early in the illness
    • Duration of virus excretion varies among different illnesses
      • Throat of adults with common cold: 1 – 3 days
      • Throat, stool, and eye for pharyngoconjunctival fever: 3 – 5 days
      • Eye for keratoconjunctivitis: 2 weeks
      • Throat and stool of children with respiratory illnesses: 3 – 6 weeks
      • Urine, throat and stool of immunocompromised patients: 2 – 12 months
  • LABORATORY DIAGNOSIS
    • Virus isolation in cell culture
    • DNA hybridization or restriction endonuclease digestion
    • PCR
    • Electron microscopy
    • ELISA
    • Latex agglutination
    • Serology
  • TREATMENT No specific treatment for adenovirus infections
  • PAPOVAVIRUSES
  • PROPERTIES
    • Virion :
      • Non-enveloped; icosahedral, 55 nm diameter
    PAPILLOMA VIRUS
  • PROPERTIES
    • Composition :
      • DNA (10%), protein (90%)
    • Genome:
      • Double stranded DNA, circular, MW 5 million, 8 kbp
  • PROPERTIES
    • Replication :
      • Nucleus
      • Highly tropic for epithelial cells of the skin and mucous membranes
      • Viral nucleic acid found in basal stem cells
      • Late gene expression (capsid proteins) restricted to uppermost layer of differentiated keratinocytes
  • PROPERTIES
    • Classification :
      • Based on:
        • DNA sequence homology
        • Tissue tropism – cutaneous or mucosal
        • Association with oncogenes
  • PROPERTIES
    • Outstanding characteristics :
      • Stimulate cell DNA synthesis
      • Restricted host range and tissue tropism
      • Significant cause of human cancer, especially cervical cancer
      • Viral oncoproteins (E6 and E7) interact with cellular tumor suppressor proteins (p53 & p105RB)
      • Cause lytic infections in permissive cells
      • Can immortalize (transform) non-permissive cells
  • PATHOGENESIS
    • Infect squamous epithelial cells  induce a characteristic cytoplasmic vacuole ( koilocyte )  hallmark of infection
    • MOT:
      • Direct contact
      • Sexual contact
      • Passage through infected birth canal
  • PATHOGENESIS Squamous epithelium of skin (warts) & mucous membrane (genital, oral & conjunctival) (+) epithelial proliferation Hand, foot, throat, eyes, cervix Local multiplication Resolution (latency) Cell transformation
  • CLINICAL
    • Wart (HPV-1 to HPV-4)
      • Benign, self-limited  spontaneous regression
      • Infect keratinized surfaces (hand and feet)
    • Benign head and neck tumors (HPV 6 and 11)
      • Oral papilloma
        • Most common benign epithelial tumor of oral cavity
        • Any age group; usually solitary
  • CLINICAL
      • Laryngeal papilloma
        • Most common benign epithelial tumor of larynx
        • May be life-threatening due to obstruction to airway
        • May extend down the trachea & into the bronchi
  • CLINICAL
    • Anogenital
      • Condyloma acuminata
      • Squamous epithelium of external genitalia & perianal areas
      • Rarely become malignant in healthy people
    • Cervical dysplasia and neoplasia
      • HPV 16 and 18
  • CLINICAL Association of HPV with Clinical Lesions HPV TYPE CLINICAL LESION SUSPECTED ONCOGENIC POTENTIAL 1, 4 Plantar warts Benign 2,4,26,27,29 Common warts Benign 3,10,28,41 Flat warts Rarely malignant 5,8 Epidermodysplasia verruciformis in patients w/ CMI deficiency 30% progress to malignancy 6,11 Anogenital condylomas; laryngeal papillomas; dysplasias and intraepithelial neoplasias Low
  • CLINICAL HPV TYPE CLINICAL LESION ONCOGENIC POTENTIAL 7 Hand warts of meat and animal handlers Benign 9,12,14,15,17,19-25, 36,46,47 Epidermodysplasia verruciformis Some progress to CA (eg, HPV-17, HPV-20) 13, 32 Oral focal epithelial hyperplasia Possible progression to CA 16,18,30,31,33 35,39,45,51,52 56 High-grade dysplasias & CA of genital mucosa; laryngeal & esophageal CA High correlation with genital & oral CA 34,40,42-44, 53-55, 58, 59, 61,62,64 66-69 Intraepithelial neoplasias (genital, other mucosal sites) Some progress to CA 75,77 Common warts in organ transplant patients 37 Keratoacanthoma Benign
  • CLINICAL COMMON WART
  • CLINICAL FLAT WARTS
  • CLINICAL PLANTAR WARTS
  • CLINICAL MULTIPLE WARTS SUBUNGUAL WART
  • CLINICAL LABIAL CONDYLOMA
  • CLINICAL INTERGLUTEAL CONDYLOMA
  • LABORATORY DIAGNOSIS
    • Histologic examination of tissues
      • Hyperkeratosis, koilocytosis
    • Pap smear
      • (+) koilocytosis
    • DNA molecular probes & PCR – method of choice
  • PROPERTIES POLYOMA VIRUS
    • Virion:
      • Non-enveloped, icosahedral, 45 nm diameter
    • Composition:
      • DNA 10%, protein (90%)
    • Genome:
      • Double-stranded, circular, MW 3 million, 5 kbp
  • PROPERTIES
    • Replication:
      • Nucleus
    • Classification:
      • Humans: BK and JC viruses
      • Simian SV40 & murine polyoma – models of tumor-causing viruses
  • PROPERTIES
    • Outstanding characteristics:
      • Stimulate cell DNA synthesis
      • Viral oncoproteins (large T and small t) interact with cellular tumor suppressor proteins (large T – p53 & pRB; small t – PP2A or protein phosphatase 2A)
      • Can cause human neurologic & renal disease
      • May cause human cancer
  • PROPERTIES
    • Outstanding characteristics:
      • Establish persistent and latent infections in kidneys and lungs
      • Large T (transformation) antigen:
        • Binds to DNA  control early & late gene transcription and viral DNA replication
        • Inactivates p53 & p105RB  (+) cell growth
  • PATHOGENESIS INHALATION Multiplication in RT Primary viremia KIDNEYS Transient secondary viremia IMMUNOCOMPETENT IMMUNODEFICIENT Latent indefinitely in kidney BK virus – urinary tract Hemorrhagic cystitis JC virus – CNS PML
  • CLINICAL
    • BK and JC viruses widely distributed in human populations  (+) specific antibody in 70-80% of adult sera
    • Infection usually occurs in childhood
    • Both may persist in the kidneys of healthy individuals but may reactivate when immune response is impaired
    • Reactivation: renal transplantation or during pregnancy
  • CLINICAL
    • Primary infection
      • Asymptomatic
    • Pregnancy
      • Reactivation
    • BK virus
      • Hemorrhagic cystitis, nephropathy, and severe renal allograft dysfunction
      • Cause of polyomavirus-associated nephropathy in renal transplant patients
  • CLINICAL
    • Progressive multifocal leukoencephalopathy (PML)
      • JC virus; subacute demyelinating disease
      • Impaired speech, vision, coordination and mentation  paralysis of arms & legs  death
      • Normal CSF findings
  • PARVOVIRUS
  • PROPERTIES
    • Virion:
      • Icosahedral, 18-26 nm diameter, 32 capsomeres; non-enveloped; extremely resistant to inactivation but can be inactivated by formalin,  -propiolactone, and oxidizing agents
    • Composition:
      • DNA (20%), protein (80%)
  • PROPERTIES
    • Genome:
      • Single-stranded DNA, linear, 5.6 kbp, MW 1.5-2.0 million
    • Classification:
      • Parvovirinae – vertebrates
        • Parvovirus & Erythrovirus – replicate autonomously in rapidly dividing cells
        • Dependovirus – depend on a helper virus (adenovirus or herpesvirus) for replication
      • Densovirinae – insects
  • PROPERTIES
    • Replication:
      • Nucleus
      • Dependent on functions of dividing host cells
    • Outstanding Characteristics:
      • Smallest DNA virus
      • Human pathogen, B19, has tropism for rbc progenitors
  • PROPERTIES
    • Parvovirus B19
      • Only one serotype
      • Replicates in mitotically active cells
      • Highly tropic for human erythroid cells
      • Cellular receptor: blood group P antigen  expressed on mature rbc, erythroid progenitors, megakaryocytes, endothelia cells, placenta, and fetal liver and heart
      • Do not have the ability to stimulate resting cells to initiate DNA synthesis
  • PATHOGENESIS Virus in URT Local replication Viral replication in erythroid precursor cells in BM Viremia Rash & arthralgia (erythema infectiosum) Normal host (slight drop in hemoglobin) Host with chronic hemolytic anemia Aplastic crisis
  • PATHOGENESIS
    • Principal target: immature cells in erythroid lineage
    • Major site of virus replication: adult marrow and fetal liver
    • Induce virus-specific IgG and IgM antibodies
    • MOT:
      • Respiratory route – major mode
      • Parenteral – blood transfusion or infected blood products
      • Vertically – mother to fetus
  • CLINICAL
    • Erythema Infectiosum (Fifth Disease)
      • Most common; I.P. = 1-2 weeks
      • Children, especially elementary school age
      • Rash on cheeks (slapped cheek appearance)  arms and legs (lace-like rash)
      • Joint involvement prominent in adults – hands and knees – mimic rheumatoid arthritis
  • CLINICAL
  • CLINICAL
    • Transient Aplastic Crisis
      • Complicate hemolytic anemia – patients with sickle cell disease, thalassemias, and acquired hemolytic anemias in audlts
      • Also occur after BM transplantation
      • Abrupt cessation of rbc synthesis in BM
      • Symptoms occur during viremic phase of infection
  • CLINICAL
    • Infection in immunodeficient patients
      • Cause chronic depression of BM and chronic anemia in immunocompromised patients
      • Disease called pure red cell aplasia
      • Severe anemia  dependent on blood transfusions
      • Observed in patients with congenital immunodeficiency, malignancies, AIDS and organ transplants
  • CLINICAL
    • Infection in pregnancy
      • If mother seronegative, pose serious risk to fetus  hydrops fetalis (anemia + CHF)
      • Fetal death occurs most commonly before the 20 th week of pregnancy
      • If mother seropositive  no adverse effect on fetus
      • No evidence of physical abnormalities
  • LABORATORY
    • PCR – most sensitive; detected in serum, blood cells, tissue samples, and respiratory secretions
    • Serology
      • B19 IgM antibody – recent infection; present 2-3 months after infection
      • B19 IgG antibody – chronic infection; persists for years
  • TREATMENT
    • Fifth disease and transient aplastic crisis – treat symptomatically
    • Aplastic crisis – require transfusion therapy
    • Commercial Ig preparations – can cure or ameliorate persistent B19 infections in immunocompromised patients and those with anemia
    • Dependovirus
      • Adeno-associated viruses
      • Commonly infect humans but replicate only in association with a second “helper” virus, usually Adenovirus
      • Neither cause illness or modify infection by their helper viruses
      • Can integrate into the host chromosome  good candidate for use in gene replacement therapy