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Adenoviruses Adenoviridae

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Adenoviruses Adenoviridae Powered By Docstoc
					Adenoviruses                                   Adenoviridae

 • Characteristics
    – double stranded DNA viruses; linear molecular
    – non-enveloped, icosa hedral particles 70 - 90 nm
    – vertices exhibit viral attachment protein(VAP) as fibers or spikes
        • possess hemagglutinin, and type-specific viral antigen
        • capsid proteins are toxic to host cell and may inhibit cellular synthesis
    – viral genome encodes many viral proteins
        • early proteins promote the growth the infected cell
             – E1A/E1B viral proteins bind and inactivate cellular p53 and
                RB(p1050 genes, thus stimulating cells growth
        • virus also provides its own DNA dependent DNA polymerase
        • some viral proteins suppress the host immune response including
          inflammation
        • late proteins provide structural proteins and those carried in mature
          virion
    – viral cycle takes 32 - 36 hours and produces 10, 000 virions
        • virus enters the cell by endocytosis, lyses the endosomal vesicle, and
          capsid is removed as it delivers the DNA to the nucleus
    – 51 human adenoviruses in groups A - F
        • based upon DNA homology, disease tropism, and fiber antigens
Trophisms of Adenoviruses
 • Pathogenesis
    – Permissive cells which best replicate adenoviruses tend to
      be from epidthelial (ectodermal) origin.
        • viruses infect lymphoid tissues, respiratory epithelium,
          gastrointestinal epithelium, and conjunctiva
        • permissive cells will ultimately exhibits lysis and death
             – most of the above mucoepithelial diseases result
               from cell lysis
    – non-permissive cells exhibit latency
        • mostly in lymphoid tissues like tonsils, adenoids, or
          Peyers patches
    – rodent cells infected with human adenoviruses become
      malignant
    – Viremia is not commom, but may occur in
      immunocompromised individuals: also recurrence from
      latency may occur as a result of immunocompromise.
  Pathogenesis of Adenovirus Infections

• Cytopathology
   – dense, central, intranuclear inclusion bodies
     composed of DNA and protein
       • associated mostly with epithelial cell necrosis
         and mononuclear cell infiltrates
   – no cellular enlargement(cytomegaly) as seen in
     other DNA viruses
• Immune Avoidance Mechanisms
   – blocks the stimulation of anti-viral protein by
     interferon
   – prevent expression of class I major
     histocompatibility antigen on the surface of
     macrophages, Thus no processed antigen is
Adenovirus Diseases/Infections
 Acute febrile pharyngitis               Serotypes 1 -7
          • nasal congestion, cough, coryza, malaise, fever, myalgia, and
             headache
          • pharyngitis       (with no other symptoms often mimic
             Streptoccal disease)
 • Pharyngoconjunctival fever                     Serotypes 1 -7
          • pharyngitis accompanied by conjunctivitis
     – Acute Respiratory Infection                often mimic the common cold
          • fever, cough, pharyngitis, cervical adenitis, laryngitis, croup,
             and bronchiolitis
               – remember the common cold seldom has fever
 • Epidemic Keratoconjunctivitis
          • follicular conjunctivitis in which the mucosa of the palpebral
             (eyelid) conjunctiva becomes pebbled or nodular and inflamed
 • Gastroenteritis and Diarrhea          Acute viral gastroenteritis
          • enteric adenovirues                   group F(serotypes 40, 41, 42)
     – Systemic Infection in Immunocompromised Patients
     – Acute Hemorrhagic Cystitis
Diagnosis of Adenovirus Disease

 • Diagnosis          clinical and epidemiological
    – viral antigen detection
    – host antibody response
    – viral culture
    – cytopathatic effects
 Epidemiology of Human Adenoviruses

• Epidemiology
  – many variations of the person-to-person, mode of
    transmission
     • respiratory droplet(aersol), close contact, fecal-oral,
       fomite
  – a non-enveloped virus which is stable to drying,
    detergents, GI secretions, choline, including
    chlorinated swimming pools
• Immunity
  – specific humoral immunity (antibody) in response
    to lytic infections is necessary for resolution and
    prevention of re-infection
  – cell mediated immunity in necessary to prevent
    viral spreading or outgrowth
Herpeviruses                                  Herpesviridae

 • Characteristics
    – large enveloped, double stranded DNA viruses
    – genome encodes for proteins which regulate viral m-RNA synthesis
      by the cells DNA dependent RNA polymerase
    – genome also encodes for proteins which regulate viral DNA
      replication
        • provide for their own DNA dependent DNA polymerase
    – genome also encodes proteins which slow down or stop the cells
      ability to synthesize its own DNA, RNA, and proteins
    – DNA replication and assembly occur in the nucleus
    – virus buds through the nuclear membrane, and is released from the
      cell by exocytosis or by lysis
    – herpesviruses infections can result in lysis, latent persistence, and
      oncogenesis(immortalization)
        • as a group they have a significant tendency toward latent persistence in
          semi-permissive cells
    – viruses in this group are very common
    – the host’s ability to control herpesvirus infections requires cell-
Herpesvirus Cycle
• Virus Cycle
   – viral glycoproteins(VAP’s) bind virus to host cell receptors
       • viral trophism is governed by this affinity
   – virus fuses with the host cell membrane; this removes the envelope
     and releases then nucleocapsid into the cytoplasm
   – the virus particle carries carries some enzymes and transcription
     factors which begin the replication cycle
   – nucleocapsid binds to the nuclear membrane and releases the
     genome into the nucleus of the host cell
   – early proteins facilitate transcription of viral genome and include the
     DNA dependent DNA polymerase; viral genome is transcribed by
     the cellular DNA dependent RNA polymerase
   – late proteins are structural and are synthesized after DNA is
     replicated
       • viral genome replication requires viral DNA dependent DNA
         polymerase
   – cells that promote latency restrict viral transcription of early and late
     proteins
   – cells that complete early and late protein synthesis will die
   – viruses are assembled in the nucleus and bud through the nuclear
Herpes simplex Viruses I/II
• Alpha Herpesviruses
   – pathogenesis
       • HSV can infect most types of human cells
            – infection is generally lytic in permissive fibroblasts and epithelial
               cells
            – latent infection occurs in semipermissive neurons
       • the glycoprotein receptors bind to heparin sulfate found on many cell
         membrane
       • a special fusion protein promotes the penetration into the host cell and
         loss of the envelope
       • viral particle carries several proteins
            – one initiates virus transcription; another is a cytotoxic protein and
               kinase
       • one early protein, latency-associated transcripts, inhibits viral
         replication and promotes latency in semipermissive cells
       • early protein enzymes include viral DNA dependent DNA polymerase
       • other early proteins inhibit cellular DNA and RNA synthesis: and cause
         the degradation of the cellular DNA and RNA
       • some early viral based products enable the virus to escape immune
         detection
       • after genome is replicated, late genes capsid proteins which are
Herpes simplex Viruses I/II Pathogenesis

 •   viruses infect mucoepithelial cells and establish latency in the
           innvervating neurons (semipermissive cells)
      – cause lytic infections of most cells, and latent persistence in
         neurons
           • cellular lysis(cytolysis) follows inhibition of cellular
             macromolecular synthesis, degradation of host DNA, etc
           • Cowdry type A acidophilic intranuclear inclusion bodies form
           • some strains cause syncytia formation
      – HSV -1 generally causes lesions above the waist
      – HSV -2 generally causes lesion below the waist
           • Viremia is rarely observed; except in immunocompromised pat
      – viruses enter through breaks in skin or mucous membranes
           • virus replication in mucoepithelial cells results in vesicle
             formation
                – vesicular fluid contains infectious virions
           • simultaneouly the virus infects the innervating neuron:
             trigeminal or sacral nerve
                – this establishes the basis for latency and recurrence
      – virus may move from cell-cell thus evading immune response
Herpes simplex Viruses I/II

 • Immunity
    – Humoral and cellular immunity are necessary for the HSV infection
      to be controlled and resolved
        • during the primary infection : interferon and natural killer cells limit
          spreading
             – during subsequent infections humoral antibody limits spreading
        • cytotoxic T-cells and activated macrophages resolve the current
          infection
             – these immune responses are the basis for symtoms
        • antibody directed against the glycoprotein spikes limits its
          spreading
        • since the effect of antibody may be reduced by expression of
          Fc and complement receptors, cell mediated immunity is
          required for complete resolution of the infection
 • Latent infection
    – occurs in neurons stimulated by physiological and anatomical
      stress
    – stress causes recurrence by causing reactivation of viral genome
Herpes simplex I/II- Clinical Diseases
• Herpes labialis = Fever Blisters, Cold Sores
      • clear vesicles on erythematous base, which ulcerates
         and crust over
           – mostly caused by HSV-1; sometimes HSV-2 in adults
      • often re-occurs when virus buds from sensory neuron
• Herpetic gingivostomatitis
      • complication of Herpes labialis with lesions on the
         oropharynx
      • mostly occurs in children and involves HSV-1
• Herpes pharyngitis in young adults involving HSV-1/2
• Herpetic keratitis   severe infection of the eye
      • may cause corneal damage leading to blindness
      • mostly due to re-occurrence(budding) of HSV-1 into the
         eye
• Herpetic whitlow/ gladiatorium =       cutaneous vesicles on
      the hands or body involving HSV- 1
      • wrestlers, thumb-sucking children, health care
         professionals
Herpes simplex I/II – Clinical Diseases
 • Eczema herpeticum =            primary infection of preexisting
   eczema       (dermatitis) causing spread of herpetic vesicles
       HSV-1
 • Herpes genitalis               Genital herpes
       • mostly involves HSV-2: sometimes HSV-1
       • painful, itching, vesicular lesions
            – males: glans or shaft of penis; sometime in the
              urethra
            – female:vulva, cervix(mucoid vaginal discharge),
              perianal area, inner thighs
       • accompanied by fever, malaise myalgia and sometimes
          inguinal adenitis
       • periodic recurrence involves budding of HSV-2 from the
          sacral nerve
 • Herpetic proctitis     vesicles in lower rectum and anus
 • Herpes encephalitis
       • acute febrile illness involving HSV-1
       • immunopathology causes destruction of temporal lobe
Herpes simplex 1/II – Clinical Diseases

 • HSV meningitis
       • milder neurological complication of HSV-2 infections
 • Neonatal Herpes
       • devastating and often fatal disease of newborns involving
         HSV-2
       • most often acquired “perinatally” from infected mothers
            • occasional “congenital” transmission
       • since neonatal cellular immune mechanisms are usually
         not well developed at birth, the virus disseminates to
         liver, lung, CNS, and other organs
       • Lesion develop on skin, in eyes and mouth
       • 50% mortality from viral pneumonitis or intravascular
         coagulopathy
       • 80% from dissemination to the brain resulting in
         encephalits
       Herpes simplex - Epidemiology

• HSV-1 is probably more constantly present in humans than any
  other virus
   – Most children are infected by age 3
   – Person-to-person, direct, salvia
   – Person-to-person, indirect, eating utensils
   – Most children get the virus from symptomatic or
      asymptomatic parents
• Antibodies develop following primary infection, but do not
  eliminate virus from the body =intracellular latency
   – Approx 80% of developed populations habor latent HSV-1
• HSV-2 is the third most common STD behind Chamydia and
  HPV’s
   – Person-to-person, direct, sexual
   – 40 -60 million infected persons in the U.S.
   – Only 20% of these possess detectable antibody
Herpes simplex 1/II - Epidemiology

 • Reservior is humans who have acute or asymptomatic infection
        • because of latency, a person is infected for a life time
    – HSV’s are exclusively human pathogens
    – being enveloped, they are readily inactivated by drying,
      detergents, and other adverse conditions such a the GI tract
        • Thus, are transmitted by direct contact, both sexual and
          nonsexual
        • Also fingers and exchange of oral fomites
        • may be autoinoculated from oral/genital lesions to other
          areas
 • HSV-1 is very common; as observed by symptoms an antibody
   studies
 • HSV-2 is spread most by sexual contact and is the third leading
        sexually transmitted microorganism in the U.S.
 • HSV-2 is also an etiological agent of cervical cancer, or at least
   a    cofactor along with HPV and other organisms in the
Herpes simplex 1/II - Diagnosis

 • Cytology = using scrapings from vesicles
    – Tzanck smear, Papanicolaou smear, Biopsy
         • CPE’s such a multinucleated giant cells and Cowdry type
           A intranuclear inclusions = presumptive diagnosis
 • Viral antigen detection
         • immunofluorescence or immunoperoxidase(EIA)
 • Nucleic acid detection
         • DNA hybridization
         • gene probes
 • Virus Isolation -vesicular fluid introduced into tissue cultures
   (HeLa cells), human fibroblasts, rabbit kidney) show CPE in 1 -3
   days
         • cells are enlarged”ballooned” with cell fusion creating
           giant cells or syncytia
 • Serology - only for primary infections; detects presence of
   antibody
Varicella-Zoster Virus

 • AlpHerpesVirus 3
    – Similar to HSV, but has smaller genome, replicates slowly,
      and infects a narrower spectrum of cell types
        • establishes latent infection in neurons
        • recurrent infection along innervated dermatomes
        • requires cell mediated immunity to control and prevent
        • vesicular, blister-like, lesions
    – differs from HSV in mode of transmission
        • mostly via p-p, direct, respiratory droplet
        • systemically spread by viremia through entire body
Varicella-Zoster Virus - Pathogenesis
 • Primary infection in the cells of the respiratory mucous, epithelial
   cells and fibroblasts; cell-to-cell spreading to regional lymph
   nodes
    – primary viremia( blood and lymph) moves virus to
       reticuloendothelial system
    – secondary viremia moves virus from RES via the blood
       though the entire body including the skin
 • Symptoms include fever, malaise, and pathomonic
   vesiculopustular       rash that appears in successive crops
   beginning on head/neck,         then thorax, and finally extremities
 • Virus becomes latent in semipermissive cells of dorsal root
   ganglia       and/or cranial nerve ganglia
    – antibody limits viremia spread, but cell-mediated immunity is
       required for complete resolution of infection.
    – infection in adult is more serious, than in children
         • a phenomenon associated with differences in cell-
           mediated response
Varicella-Zoster Virus – Clinical Disease

 • Shingles                      Herpes zoster
       • is a recurrent manifestation of VZV acquired earlier in life
          as chickenpox
       • virus buds through the nerves along the thoracic
          dermatomes or along the trigeminal nerve
       • painful vesicular lesions having an erythematous
          basedevelop along these nerves
 • Postherpetic neuralgia
       • chronic pain along the dermatomes which persists from
          years following a bout of shingles
       • occurs in 30% of patients older than 65 year of age
Varicella-Zoster Virus – Clinical Disease

 • Chickenpox            classic childhood exanthem
       • a mild childhood disease with symptoms of fever and
         maculopapular rash which follows a 14 day incubation
         period
       • the vesicle is the hallmark of Varicella
           – maculopapular lesion forms a thin walled vesicle(dew
              drop) - 2-4 mm
           – vesicle becomes pustular and crusts over forming a
              scab
           – successive crops of vesicles appear over 3-5 days;
              at any given time all stages of skin lesions can be
              observed
       • lesions are generalized beginning on the scalp,
         spreading over face and neck to the trunk where they are
         most severe and noticable
           – lesions may also appear on mucous membrane of
              the mouth, conjunctiva, and vagina
           – rash may hemorrhage in cases of thrombocytopenia
Varicella-Zoster - Diagnosis

 • Cytology
    – Cowdry type A intrnuclear inclusion bodies in infected cells
        • also syncytia observed
        • Tzanck smears from base of vesicles reveal
           multinucleated giant cells (syncytia
 • Antigen detection from skin lesions, biopsy specimens
        • Direct florescent antibody - most sensitive
 • Virus isolation in human diploid fibroblasts   = CPE
 • Serology
        • presence of IgM or four fold increase in IgG
             – ELISA is most quantitative
   Varicella- Zoster Virus - Epidemiology

• Epidemiology
   – Chickenpox
      • VZV is extremely communicable
      • Reservoir = infected humans either symptomatic or
        asymptomatic
      • Primary Mode of Transmission = p-p, direct, respiratory
        droplet
      • Secondary Route = direct contact with active vesicles
   – Shingles
      • Is a reactivation disease; resulting from previous VZV
        infection
      • Is generally not considered a communicable condition
• Exception
   – There are a few documented cases of transmission from and
     adult with shingles to a young child
      • Child developed chickenpox
        Varicella-Zoster Virus - Control

• Chickenox
   • Isolation of Infected Individuals
   • Active Attenuated Vaccine or VZV immunue globulin
       • induces both humoral and cell-mediated immunity
• Shingles
   – Theoretically, control of chickenpox should reduce latency in
     neurons and ultimately reduce the amount of re-current
     symptoms in the form of shingles
Epstein-Barr Virus - Characteristics
 • Gammaherpes Virus
 • very limited host range and tissue trophism
    • range is defined the C3d complement receptor
    • C3d is expressed on B-cells, and epithelial cells of the
      oropharynx nasopharynx, and salivary glands
   Epstein-Barr Virus – Clinical Diseases

• Infectious Mononucleosis
   • high fever, malaise, pharyngitis, lymphadenopathy, and often
      hepatosplenomegaly: occasional rash
            • lymphocytosis
            • heterophile postive
   • most common complaint is fatigue
   • generally mild or symptomatic in children
   • most severe in adolescents and adults
   • often referred to as “heterophile positive” mononucleosis
       • sometimes has neurological complications
            • Meningoencephalitis; Guillan-Barre’Syndrome
   • Incubation period = 30-60 days
       • Carriers shed virus for weeks, sometimes months
   • Symptoms last 2-4 weeks; T-cells self-limits disease
Epstein-Barr Virus – Clinical Diseases

 • Chronic “mononuclesis-like” disease
       • recurrent and cyclical
       • characterized by chronic fatigue
 • Lymphoproliferative Diseases
    • Hairy Oral Leukoplakia = unusual presentation of EBV
       productive infection of the epithelial cells of the
      mouth/tongue in immunocompromised patients
    • Burkitts Lymphoma          AfBL
            • monoclonal B-cell lymphoma of the jaw and face due
              to immortalization of B-cells
            • malaria seems to enhance this manifestation in
              Africa
            • mostly seen children
            • tumors express EBNA-1 viral antigen; lymphocyte
              derived tumors
Epstein-Barr Virus – Virus Cycle

 • Virus transcription pattern governs the outcome of infection
    – Lytic infection
             • occurs in permissive cells; mostly respiratory
               epithelial cells
             • ZEBRA protein activates early genes
             • virus provides for its own DNA dependent DNA
               polymerase
             • several glycoproteins synthesized and incorporated
               into the nuclear membrane
             • virus is released by lysis
             • Infected cells express “Late antigens”
                  » Viral capsid antigen
                  » Viral envelope glycoproteins
         Epstein-Barr Virus – Virus Cycle

• Latent infection
   – The major target cell for EBV is the B-lymphocyte
       • B-cells become transformed or immortalized and begin a
         pattern of uncontrolled cell division
   • infected cell contain a small number of circular plasmid-like
     EBV genomes which are replicated when the cell is actively
     dividing
       • in this cycle several viral coded proteins are produced
         which promote latency, immortalization, and sometimes
         oncogenesis
                » EBNA’s
                » latent proteins (LP)
                » latent membrane proteins (LMP)
                » EBER - Epstein Barr Encoded RNA
       • occurs in semi-permissive B-cells
            – <10% of immortalized cells release active virions
Epstein-Barr Virus- Pathogenesis

 • Productive infection of epithelial cells in the oropharynx
     – virus is shed into lymphatics and blood and infects B-cells
     – Basis of pharyngitis
 • EVB binds to the C3d receptors on B-lymphocytes, penetrates
   into the cells by fusion, DNA is released into the nucleus, and
   immediately establishes a condition of latency most as extra-
   chromosomal episomes.
 • Infected cells initiate the cells cycle, begin to synthesize DNA
   (including viral DNA), and begin to divide rapidly by mitosis
     – infected immortalized cells synthesize many EBV products
         • EBNA’s = nuclear antigens(6)
         • LMP’s = latent membrane proteins(2)
         • EBER = virus specific RNA’s(2)
      Epstein-Barr Virus - Pathogenesis

• Infectious mononucleosis
   – B-cells are immortalized and continue to divide
       • EBV is a B-cells mitogen which stimulates growth and
          prevent apoptosis
   – B-cells become the site of latent infection
   – EBV alters the way B-cells interact with the immune system
       • increases the expression of B-cell surface proteins
       • EBV infected B-cells express antigens which activate T-
          cells
            – The classical lymphocytosis of this condition is the
               result of the proliferation of atypical lymphocytes =
               Downey Cells
                 » lymphocytosis = 10 -80% of white cells are
                   atypical
                 » the increased T-cells cause swelling of lymph
                   nodes, spleen, liver
   – Mononucleosis results from the interaction of infected B-cells
      with activated T-cells
       • Activated T-cells are essential for the resolution of the
Infectious Mononucleosis - Diagnosis

 • symptoms
    – Lymphcytosis = 60 - 70% mononuclear cells with 30 %
       atypical lymphocytes = earliest indicator of disease
 • Virus detection
    – Nucleic acid hydridization to detect EBV RNA’s
    – antigen detection – on epithelial cells in throat washings
    – serology
             – heterophile antibody         infected B-cells produce
               an IgM heterophile antibody which reacts with the
               Paul-Burnell antigen on sheep, horse, and bovine
               erythrocytes
                 » antibody is present by end of first week and is
                   an excellent indicator of EBV infection in adults;
                   not reliable in children
                 » ELISA test used for detection
             – other tests for antibody against viral capsid proteins
Epstein-Barr Virus - Epidemiology

 • Reservoir is Humans ( symptomatic or asymptomatic)
 • Person-to-Person = mode of transmission = respiratory droplet
    – EBV is transmitted in salvia
        • more than 90% of infected individuals shed virus
          intermittently for life
        • children often become infected at an early age by sharing
          drinking glasses
        • Disease is generally subclinical in children
    – disease in correctly called the “kissing disease” because of it
      increased incidence in adeloscents who exhange salvia.
        • approx. 70% of the U.S. population is infected by age 30
    – Transplant recipients who are immunocompromised have a
      high risk for immuno-proliferative disease

				
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